Successful treatment of steroid-resistant Weber–Christian disease with biliary ductopenia using cyclosporin A

M. Hinata, T. Someya, H. Yoshizaki, K. Seki1 and K. Takeuchi

Department of Gastroenterology and 1 Department of Pathology, Toranomon Hospital, Tokyo, Japan

Correspondence to: M. Hinata, Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-0001, Japan. E-mail: mhinata{at}hotmail.com

SIR, Weber–Christian disease (WCD) is an unusual idiopathic disorder characterized by non-suppurative nodular panniculitis with fever and cutaneous lesions [1]. The aetiology of WCD remains unknown, and systemic WCD, associated with severe liver damage, is often fatal [2]. Hepatic injury associated with WCD is characterized by steatohepatitis [3, 4]. To our knowledge, however, WCD with biliary ductopenia has not yet been reported. We report the first case of systemic WCD with biliary ductopenia that was successfully treated with cyclosporin A (CyA).

The patient was a 27-yr-old Japanese man with recurrent episodes of subcutaneous nodules on both legs since 1995. In January 1998 he was admitted to the Department of Dermatology at our hospital because of a middle-grade fever, bilateral pitting oedema and subcutaneous nodules. Laboratory tests showed the following results. A complete blood count revealed a leucocyte count of 2.3 x 103/µl (89% band cells, 6% lymphocytes, 2% monocytes). Haemoglobin level was 10.7 g/dl and haematocrit 33.5%. Platelet count and coagulation tests were normal. The patient was found to have severe malnutrition with extremely low serum concentrations of total protein and albumin (5.8 and 2.3 g/dl, respectively). The serum concentrations of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, {gamma}-glutamyl transpeptidase and creatine kinase were elevated to 173, 74, 1506, 745, 113 and 199 IU/l, respectively. The serum concentrations of total bilirubin (T-Bil), pancreatic enzymes and {alpha}1-antitrypsin were within the normal range. Serum ferritin level was markedly increased (34 783 ng/dl). ANA was positive, while the other antibodies and microbiological tests were negative. A small amount of bilateral pleural effusion, moderate fatty liver, a moderate amount of ascites and diffuse intestinal oedema were detected by abdominal ultrasonography or CT. Bone marrow aspirate showed no histiocytic infiltration. A skin biopsy showed panniculitis, which included infiltration of lymphoid cells and granulomatous inflammation of epithelioid cells. He was diagnosed with WCD and treated unsuccessfully with pulse steroid therapy (intravenous methylprednisolone, 1 g/day for 3 days). He was transferred to our department because of his worsening clinical condition and laboratory tests (Fig. 1A). Gastrointestinal bleeding associated with disseminated intravascular coagulation (DIC) and severe jaundice were observed. T-Bil and soluble interleukin-2 receptor (sIL-2R) concentrations were extremely high at 23.5 mg/dl and 13 500 U/ml, respectively. In February 1998, the patient was treated with intravenous CyA and plasma exchange therapy, achieving a plasma CyA concentration of 100 ng/ml. Three weeks later oral CyA therapy (225 mg/day) was started instead of intravenous CyA infusion because of almost complete recovery. Before steroid therapy, a liver biopsy showed periportal steatosis with granulomatous changes and reduction of bile ducts, biliary ductopenia, infiltration of inflammatory cells and severe fatty changes around the portal vein area (Fig. 1B). However, CyA therapy significantly improved the liver histopathology (Fig. 1C), with reduction of inflammatory cell infiltration and periportal steatohepatitis, and regeneration of small bile ducts. Based on this improvement, CyA and corticosteroid treatment was discontinued in 1999. He has been symptom-free and has maintained a normal life style for more than 5 yr without CyA and steroids.




View larger version (87K):
[in this window]
[in a new window]
 
FIG. 1. (A) Clinical course. mPSL, methylprednisolone; PSL, prednisolone; i.v., intravenous infusion; p.o., per os; T-Bil, total bilirubin; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; sIL-2R, soluble interleukin 2 receptor. (B) High-power photomicrographs of liver histopathological findings prior to steroid pulse therapy. Note the presence of periportal steatohepatitis with infiltration of neutrophils, lymphocytes and macrophages. Note also the lack of bile ducts (haematoxylin–eosin stain, x100). (C) High-power photomicrographs of liver histopathological findings 40 days after commencement of CyA therapy. Note the reduction in hepatic steatosis and infiltrated lymphoid cells and histiocytic cells, and the significant increase in the number of bile ducts (arrows) in comparison with panel B (haematoxylin–eosin stain, x400). Parts (B) and (C) of this figure may be viewed in colour as supplementary data at Rheumatology Online.

 
WCD is a primary panniculitis, which is a histiocytic disorder described as a form of lobular panniculitis with infiltration of haemophagocytic benign histiocytes [1]. In our patient, the diagnosis of WCD was made based on the clinical features, histopathological findings of the skin and liver biopsy specimen. His WCD was steroid-resistant and he developed several complications, including DIC and severe jaundice, after steroid pulse therapy. However, CyA was remarkably effective and the clinical condition showed almost complete recovery except for mild fatty liver. Successful treatment of WCD with CyA was first described in 1987 [5] and several additional reports described a similar response to CyA [6–9]. The aetiology of WCD remains unknown. However, it has been related to an immunologically mediated reaction because of sIL-2R elevation [8, 9]. In the present case, we also observed high serum concentration of sIL-2R, which represents T-cell activation, and successful response to CyA, which acts primarily on helper T cells and interferes with the production of various cytokines. CyA therapy resulted in a dramatic decrease in the serum concentration of sIL-2R followed by rapid clinical improvement.

In addition, a striking feature of this case was the hepatic involvement. Liver biopsy before steroid pulse therapy showed periportal steatohepatitis with biliary ductopenia. Ductopenia is a rare cause of prolonged, progressive cholestatic liver disease [10]. It is mainly associated with chronic allograft rejection, graft-versus-host disease, primary biliary cirrhosis, drugs and toxins. Ductopenia associated with WCD is rare and our report is the first to describe ductopenia as one of the pathological features of WCD and to show that CyA is significantly effective in ductopenia associated with steroid-resistant WCD.

In conclusion, we report a case of WCD with biliary ductopenia successfully treated with CyA. Ductopenia should be included as a possible pathophysiological factor of hepatic lesion in WCD.

The authors have declared no conflicts of interest.

References

  1. Panush RS, Yonker RA, Dlesk A, Longley S, Caldwell JR. Weber–Christian disease. Analysis of 15 cases and review of the literature. Medicine (Baltimore) 1985;64:181–91.[ISI][Medline]
  2. Aronson IK, West DP, Variakojis D, Malkinson FD, Wilson HD, Zeitz HJ. Fatal panniculitis. J Am Acad Dermatol 1985;12:535–51.[ISI][Medline]
  3. Kimura H, Kako M, Yo K, Oda T. Alcoholic hyalins (Mallory bodies) in a case of Weber–Christian disease: electron microscopic observations of liver involvement. Gastroenterology 1980;78:807–12.[ISI][Medline]
  4. Wasserman JM, Thung SN, Berman R, Bodenheimer HC, Sigal SH. Hepatic Weber–Christian disease. Semin Liver Dis 2001;21:115–8.[CrossRef][ISI][Medline]
  5. Entzian P, Barth J, Monig H, Ohnhaus EE, Kirch W. Treatment of Weber–Christian panniculitis with cyclosporine A. Rheumatol Int 1987;7:181.[CrossRef][ISI][Medline]
  6. Usuki K, Kitamura K, Urabe A, Takaku F. Successful treatment of Weber–Christian disease by cyclosporin A. Am J Med 1988;85:276–8.
  7. Ostrov BE, Athreya BH, Eichenfield AH, Eichenfield AH, Goldsmith DP. Successful treatment of severe cytophagic histiocytic panniculitis with cyclosporine A. Semin Arthritis Rheum 1996;25:404–13.[CrossRef][ISI][Medline]
  8. Nakane S, Kawabe Y, Eguchi K et al. A case of cytophagic histiocytic panniculitis: successful treatment of recurrent attacks with steroid pulse therapy and oral cyclosporin A. Clin Rheumatol 1997;16:417–21.[ISI][Medline]
  9. Iwasaki T, Hamano T, Ogata A, Hashimoto N, Kakishita E. Successful treatment of a patient with febrile, lobular panniculitis (Weber–Christian disease) with oral cyclosporin A: implications for pathogenesis and therapy. Intern Med 1999;38:612–4.[ISI][Medline]
  10. Engler S, Elsing C, Flechtenmacher C, Theilmann L, Stremmel W, Stiehl A. Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders. Gut 2003;52:688–93.[Abstract/Free Full Text]
Accepted 14 January 2005





This Article
Full Text (PDF)
Supplementary data
All Versions of this Article:
44/6/821    most recent
keh576v2
keh576v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Hinata, M.
Articles by Takeuchi, K.
PubMed
PubMed Citation
Articles by Hinata, M.
Articles by Takeuchi, K.
Related Collections
Other Rheumatology