Case Report Idiopathic Cholestasis as a Paraneoplastic Phenomenon in Hodgkin’s Lymphoma Stefan K. Barta,1 Joachim Yahalom,2 Jinru Shia,3 Paul A. Hamlin4
Abstract Paraneoplastic cholestasis is an uncommon presenting symptom in Hodgkin’s lymphoma (HL). Two distinct entities causing this clinical picture have been described: idiopathic cholestasis and vanishing bile duct syndrome (VBDS). We report a patient with idiopathic cholestasis and early-stage HL with favorable risk factors whose liver biopsy results were consistent with intrahepatic cholestasis and no ductopenia. Other causes for cholestatic jaundice were ruled out. He was treated with subtotal lymphoid irradiation and subsequently experienced a steady improvement in his liver function tests to near normal over 21 months. This case illustrates a rare paraneoplastic phenomenon, and a review of the available literature is included. We also discuss the differences between HL-related idiopathic cholestasis and VBDS. The distinction between these 2 diseases has prognostic implications: idiopathic cholestasis is usually reversible in early-stage HL after treatment, whereas patients who develop VBDS commonly die from their disease. There is no established approach to the management of paraneoplastic cholestasis. We postulate that single-modality radiation therapy alone should be considered a valid treatment alternative in early-stage HL with idiopathic cholestasis.
Clinical Lymphoma & Myeloma, Vol. 7, No. 1, 77-82, 2006 Key words: Hepatitis, Jaundice, Radiation, Vanishing bile duct syndrome
Introduction The frequency of hepatic involvement in Hodgkin’s lymphoma (HL) varies widely. At the time of diagnosis, the reported incidence of liver involvement is between 3% and 14%, whereas in autopsy series, the range is as high as 30%-70%.1-3 Cholestasis as the presenting symptom of HL is uncommon (< 4%).4 The pathophysiologic mechanisms causing cholestasis include direct intrahepatic parenchymal or biliary epithelial involvement, extrahepatic biliary obstruction secondary to lymphadenopathy, or concurrent unrelated causes such as viral hepatitis, previous underlying liver disease, or drug toxicities. Additionally, a small minority of patients present with intrahepatic cholestasis caused by a paraneoplastic phenomenon.1,5-24 These can be divided on liver biopsy into 2 different groups: those identified as consistent with having vanishing bile duct syndrome (VBDS) or those with pure intrahepatic cholestasis with no discernible ductopenia. Herein, we report upon a patient who presented with cholestatic hepatitis and was subsequently diagnosed with 1Department
of Medicine, St. Luke’s Roosevelt Hospital Center, New York of Radiation Oncology 3Department of Pathology 4Department of Medicine – Lymphoma Service Memorial Sloan-Kettering Cancer Center, New York, NY 2Department
Submitted: Nov 3, 2005; Revised: Mar 24, 2006; Accepted: Apr 19, 2006 Address for correspondence: Paul A. Hamlin, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 Fax: 646-422-2164; e-mail:
[email protected]
HL. Thorough clinical, laboratory, and pathologic evaluation was consistent with idiopathic cholestasis and concurrent extrahepatic HL. We offer this demonstrative case as a forum to discuss the management options and review the available literature regarding this rare phenomenon.
Case Report A 41-year-old man presented with a 4-day history of nausea, anorexia, diarrhea, and jaundice. His physical examination was remarkable only for scleral and subungual icterus. He had taken celecoxib 2 weeks before for 5 days but otherwise denied taking any other medication, over-the-counter drugs, or herbal remedies. He reported no history of alcohol abuse or blood transfusions. Initial biochemical results were significant for a cholestatic and hepatitic picture: total bilirubin 8.3 mg/dL, direct bilirubin 5.6 mg/dL, alkaline phosphatase 244 IU/L, aspartate aminotransferase 203 IU/L, alanine aminotransferase 712 IU/L, and albumin 4.1 g/dL. Baseline complete blood cell count was normal, International Normalized Ratio 0.98, erythrocyte sedimentation rate 38 mm per hour, and lactate dehydrogenase 710 IU/L. Serology results to exclude hepatitis A, B, and C were negative, as was polymerase chain reaction for hepatitis B and C. Test results for HIV types 1 and 2, human T-cell leukemia virus types 1 and 2, antinuclear autoantibodies, antimitochondrial antibodies, antismooth-muscle and antiliver/ kidney microsomes antibodies, and serology for cytomegalovirus and Epstein-Barr virus were also negative; additionally, iron
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Clinical Lymphoma & Myeloma July 2006 • 77
Cholestasis in Hodgkin’s Lymphoma Figure 1 Positron Emission Tomography Scan Showing Mediastinal Areas of Increased Avidity
Figure 2 Histology of Liver Before Treatment A
B
Positron emission tomography scan revealing 2 mediastinal areas of abnormally increased avidity (arrows) indicating tissue affected by Hodgkin’s lymphoma on the right paratracheal and superior vena cava region.
and lipid studies, serum immunoelectrophoresis, angiotensinconverting enzyme, and ceruloplasmin levels were normal. The initial chest radiograph revealed a right paratracheal mass, and computed tomography of his chest, abdomen, and pelvis confirmed a right-sided 4-cm paratracheal mass in the superior mediastinum and a 3-cm mass slightly inferiorly lying anterior to the superior vena cava with no additional lymphadenopathy; liver as well as spleen were normal. Mediastinal biopsy results exhibited mixed cellularity HL (CD30+CD15+CD20–CD79a– CD3–). Bone marrow biopsy results were normal. A positron emission tomography scan demonstrated avidity in the right paratracheal and superior vena cava region only (Figure 1). Percutaneous liver biopsy results revealed mild intrahepatocellular and canalicular cholestasis associated with focal bile duct epithelial injury and a mononuclear inflammatory infiltrate. The inflammatory infiltrate was minimal in some portal tracts (Figure 2A) and more apparent in others (Figure 2B). In the lobules, there were sinusoidal dilatation, minimal mononuclear infiltration, and hepatocellular disarray. Two weeks after initial presentation, liver function test (LFT) results had further deteriorated (Figure 3), and the patient presented to our institution for recommendations regarding
78 • Clinical Lymphoma & Myeloma July 2006
(A and B) Hemotoxylin and eosin–stained section of the first liver biopsy showing interlobular bile ducts with epithelial atypia represented by pleomorphic and irregular nuclei, focal loss of nuclei, and foamy cytoplasm. Note the presence of a mononuclear infiltrate that varies from minimal (A) to modest (B).
the treatment of stage IIA favorable nonbulky HL. A magnetic resonance cholangiogram demonstrated no abnormalities. With a presumption that the cholestasis was most consistent with a secondary paraneoplastic phenomenon, the patient received a 2-week course of prednisone 100 mg, but LFTs remained abnormal. A decision to avoid chemotherapy and treat with radiation therapy alone was made. After treatment with mantle field irradiation (20 fractions, 3600 cGy) followed by a mediastinal boost (2 fractions, 360 cGy), a repeat positron emission tomography and computed tomography scan demonstrated a complete resolution of all previously fluorodeoxyglucose-avid adenopathy. The LFTs had further improved but did not normalize to allow for safe incorporation of chemotherapy. Therefore, the patient received consolidative radiation therapy to the periaortic splenic field (19 fractions, 3240 cGy) to complete subtotal lymphoid irradiation (STLI). No chemotherapy was given. After STLI, the mild
Stefan K. Barta et al Figure 4 Histology of Liver After Complete Subtotal Lymphoid Irradiation
Figure 3 Liver Function Tests and Their Relation to Treatment A
A
1200
Steroids including taper*
AlkPhos (IU/L)
Diagnosed Hodgkin’s Lymphoma† First liver biopsy‡
1000
AST (IU/L)
Radiation§
ALT (IU/L) Upper normal limit AlkPhos Upper normal limit AST and ALT
800 IU/L
Second liver biopsy
600
400
200
0 2
4
8
6
10
12
14
16
18
20
22
Months
B
B 10 TBili (mg/dL) DBili (mg/dL) Upper normal limit TBili Upper normal limit DBili
8
mg/dL
6
4
2 Hemotoxylin and eosin–stained section of the second liver biopsy showing (A) a portal tract with an intact bile duct and (B) another one with ductular proliferation and a mixed inflammatory infiltrate. March 4, 2005
Dec 4, 2004
Sept 4, 2004
June 4, 2004
March 4, 2004
Dec 4, 2003
Sept 4, 2003
June 4, 2003
0
Months (A) Treatment administered from June 4, 2003 until April 4, 2005. *July 18-August 20, 2003. †July 9, 2003. ‡July 10, 2003. §August 11-November 12, 2003 and September 30-October 24, 2003. Abbreviations: AlkPhos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DBili = direct bilirubin; TBili = total bilirubin
cholestatic hepatitis persisted. Repeat liver biopsy results 6 months after presentation showed most portal tracts containing a bile duct with only minimal reactive changes (Figure 4A). There was significantly less lobular disarray compared with the first biopsy; however, in 2 portal areas, there was bile ductular proliferation along with epithelial atypia and a mixed inflammatory infiltrate (Figure 4B). Bile pigment was identified in some liver cells. Currently, 2 years after diagnosis, the patient remains clinically well and in remission. His LFT results have demonstrated continued improvement, returning to near normal.
Discussion Paraneoplastic cholestasis represents an uncommon but challenging scenario from a diagnostic and treatment perspective. When cholestatic hepatitis is the presenting clinical picture of a patient with HL, other causes for the liver abnormalities must first be eliminated because paraneoplastic cholestasis is a diagnosis of exclusion. In this case, alternative diagnoses have been excluded, and the course is concordant with the previously described phenomenon of paraneoplastic cholestasis. Although there is no definitive test to exclude drug toxicity secondary to celecoxib25-27 as an etiology, this is unlikely given the clinical scenario of continued deterioration of the LFT for 3 weeks after discontinuation of the drug and the prolonged course.28 Generally, cholestasis related to HL can be divided into 2 subgroups according to histopathologic findings on liver biopsy: VBDS or idiopathic intrahepatic cholestasis. Vanishing bile duct syndrome is a disorder characterized by presumed autoimmune destruction of intrahepatic bile ducts. To establish the diagnosis, > 50% of the portal tracts must have no visible bile ducts. Ductopenia can be a developmental abnormality or can be caused by several mechanisms, including
Clinical Lymphoma & Myeloma July 2006 • 79
Cholestasis in Hodgkin’s Lymphoma Table 1 Previously Reported Cases of Idiopathic Cholestasis1,5-15 Patient
Reference
Stage
Liver Biopsy Result
Treatment
Liver Function
Outcome
1
Bouroncle et al (1962)5
IV
Cholestasis
Radiation therapy
Not normalized
Died 7 months, no remission
2
Bouroncle et al (1962)5
IV
Cholestasis
Radiation therapy
Not normalized
Died 8 months, no remission
3
Juniper (1963)6
IV
Cholestasis
None*
Not normalized
Died 18 months
4
Groth et al (1972)7
III
Cholestasis × 2
Chemotherapy
Not normalized
Died 5 months, no remission
5
Perrera et al (1974)8
I
Cholestasis × 2
Radiation therapy
Normal within 10 months
Remission for 10 months
6
Perrera et al (1974)8
IIA
Cholestasis
Radiation therapy
Normal within 2 months
Remission for 4 months
7
Perrera et al (1974)8
IV
Cholestasis × 2
Radiation therapy
Not normalized
Died 19 months, partial remission
8
Piken et al (1979)9
IVB
Cholestasis
Chemotherapy
Not normalized
Died 4 months, no remission
9
Trewby et al (1979)10
IV
Cholestasis × 2 (initially reported as primary sclerosing cholangitis)
None*
Improved initially with steroids, but relapsed
Died within 15 months
10
Trewby et al (1979)10
IV
Cholestasis × 2
Chemotherapy
Not normalized
Died within 3 weeks, no remission
11
Lieberman (1986)11
IV
Cholestasis
None*
Not normalized
Died 3 months
12
Birrer and Young (1987)1
IIIB
Cholestasis
Chemotherapy
Not normalized
Died after first cycle of chemotherapy
13
Warner et al (1994)12
IB
Cholestasis
Radiation therapy
Normal within 18 months
Remission for 36 months
14
Jansen and van der Lelie (1994)13
IIA
Initially cholestasis; second biopsy diffuse fibrosis
Radiation therapy
Never normalized
Remission, but died of variceal hemorrhage after 12 months
15
Yalcin et al (1999)14
IIB
Biliary type hepatocellular injury
None†
Deteriorated
Died shortly after presentation
16
Yalcin et al (1999)14
IIIB
Biliary type hepatocellular injury
Chemotherapy × 2, then radiation therapy‡
Normal within 26 months
Remission for 26 months
17
Liangpunsakul et al (2002)15
IIA
Biliary type hepatocellular injury
Chemotherapy
Normal within 2 months
Remission for 18 months
18
Present case
IIA
Biliary type hepatocellular injury × 2
Radiation therapy
Abnormal after 21 months
Remission for 21 months
Patients with idiopathic cholestasis generally have a better prognosis when presenting with stage I/II HL and when treated with radiation therapy (4 of 6 [67%] experienced remission and were alive at follow-up), whereas outcome for patients with stage III/IV disease treated with chemotherapy has been very poor (11 of 11 patients died). It has to be taken into consideration that some of the cases are from an area with less sophisticated diagnostic means, implying that, in some cases, other etiologies might have been missed. *Patient only diagnosed with Hodgkin’s disease on autopsy. †No treatment started because of severe cholestasis. ‡The patient initially received chemotherapy, but as his liver function tests deteriorated, he was switched to radiation therapy after only 2 cycles of chemotherapy.
infective, chemical, vascular, and immune-mediated processes like in primary biliary cirrhosis, primary sclerosing cholangitis, or graft rejection after liver transplantation. The bile duct loss is usually followed by progressive cholestasis, biliary fibrosis with atypical ductular proliferation, and progression to liver cirrhosis and failure. It is generally considered to be irreversible.29-30 In 1993, Hubscher et al first described 3 cases of VBDS in patients with HL.16 Since then, many more reports have been published documenting the same finding, and VBDS has been clearly established as a paraneoplastic phenomenon in HL.17-24
80 • Clinical Lymphoma & Myeloma July 2006
The histopathologic findings in idiopathic cholestasis are nonspecific and most commonly show canalicular stasis with mixed inflammatory infiltrates.15 To date, idiopathic intrahepatic cholestasis as a presenting symptom of HL has been reported in only 17 cases in available English literature.1,5-15 These 2 distinct paraneoplastic phenomena are not only different in their histologic picture, but also in their clinical course: the majority of patients with VBDS died during treatment regardless of stage, often secondary to liver failure,16-24 whereas patients with idiopathic cholestasis generally have a better prognosis when presenting with stage I/II HL and when treated with radiation
Stefan K. Barta et al therapy. Outcome for patients with paraneoplastic idiopathic cholestasis with stage III/IV disease treated with chemotherapy, unfortunately, has also been very poor, making it generally an unfavorable prognostic marker in this group (Table 1).1,5-15 The current standard of care for early-stage, favorablerisk HL includes ABVD (doxorubicin/bleomycin/vinblastine/ dacarbazine) followed by involved-field radiation or STLI for patients who are not good candidates for chemotherapy (National Comprehensive Cancer Network guidelines). Given the hepatic dysfunction present in this case, the ability to deliver full-dose chemotherapy was limited, and the potential for compounding hepatotoxicity was high, both of which would compromise curability. Hence, the possible benefits of chemotherapy versus single-modality radiation treatment were not deemed worth the potential risk.31,32 In early-stage nonbulky HL with favorable risk, failure-free survival rates ranging from 81% to 93% with STLI alone, compared with disease-free survival rates of 94%-96% with chemotherapy.33-38 The pathophysiologic mechanism of paraneoplastic cholestasis in HL remains unclear. It is speculated that a paraneoplasticrelated indirect or direct release of toxic cytokines from lymphoma cells could be responsible.16,24 In Stauffer syndrome (paraneoplastic cholestasis associated with renal cell carcinoma), increased levels of interleukin-6 have been demonstrated.39 A cytokine release would be in keeping with the fact that, often, there is a disparity between a minor volume of lymphoma and the presence of severe cholestasis, although increased interleukin-6 levels alone would not be sufficient by themselves to explain the phenomenon.40 An immune-mediated process has been postulated for VBDS, owing to similarities with other diseases causing disappearance of intrahepatic bile ducts.28,30,41-44 Similarly, idiopathic cholestasis might also represent an autoimmune process directed at the biliary endothelium, with inflammation rather than destruction as the end result. In the future, prospective measurement of various cytokine levels before and after treatment could assist in elucidating a pathophysiologic mechanism in this rare entity.
Conclusion Our case of idiopathic cholestasis associated with HL represents an uncommon clinical scenario that poses challenges in diagnosis and management decisions. Only a comprehensive workup including liver biopsy can establish a paraneoplastic phenomenon as etiology, which has to be differentiated from prognostically less favorable VBDS. In patients with earlystage HL and idiopathic cholestasis, because of the potentially detrimental hepatotoxicity of chemotherapy, radiation alone should be considered as a valid treatment alternative to the current standard of care.
References 1. Birrer MJ, Young RC. Differential diagnosis of jaundice in lymphoma patients. Seminars in Liver Disease 1987; 7:269-277. 2. Dich NH, Goodman ZD, Klein MA. Hepatic involvement in Hodgkin’s disease. Cancer 1989; 64:2121-2126. 3. Thiele DL. Hepatic manifestations of systemic disease and other disorders of the liver. In: Feldman M, Friedman L, Sleisenger MH, eds. Sleisenger and
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.
34.
Fortran’s Gastrointestinal and Liver Diseases. Philadelphia: Elsevier Science 2002; 7:1603-1604. Levitan R, Diamond HD, Carver LF. Jaundice in Hodgkin’s disease. Amer J Med 1961; 30:99-111. Bouroncle BA, Old JW, Vazques AG. Pathogenesis of jaundice in Hodgkin’s disease. Arch Intern Med 1962; 110:872-883. Juniper K. Prolonged severe obstructive jaundice in Hodgkin’s disease. Gastroenterology 1963; 44:199-204. Groth C, Hellstrom K, Hofvendahl S, et al. Diagnosis of malignant lymphoma at laparotomy disclosing intrahepatic cholestasis. Acta Chir Scand 1972; 138:186-189. Perrera DR, Greene ML, Fenster LF. Cholestasis associated with extrabiliary Hodgkin’s disease. Gastroenterology 1974; 67:680-685. Piken EP, Abraham GE, Hepner GW. Investigation of a patient with Hodgkin’s disease and cholestasis. Gastroenterology 1979; 77:145-147. Trewby PN, Portmann B, Brinkley DM, et al. Liver disease as presenting manifestation of Hodgkin’s disease. Quart J Med 1979; 189:137-150. Lieberman DA. Intrahepatic cholestasis due to Hodgkin’s disease: an elusive diagnosis. J Clin Gastroenterol 1986; 8:304-307. Warner AS, Whitcomb FF. Extrahepatic Hodgkin’s disease and cholestasis. Am J Gastroenterol 1994; 89:940-941. Jansen PL, van der Lelie H. Intrahepatic cholestasis and biliary cirrhosis associated with extrahepatic Hodgkin’s disease. Neth J Med 1994; 44:99-102. Yalcin S, Kars A, Sokmensuer C, et al. Extrahepatic Hodgkin’s disease with intrahepatic cholestasis: report of 2 cases; Oncology 1999; 57:83-85. Liangpunsakul S, Kwo P, Koukoulis GK. Hodgkin’s disease presenting as cholestatic hepatitis with prominent ductal injury. Eur J Gastroenterol Hepatol 2002; 14:323-327. Hubscher SG, Lumley MA, Elias E. Vanishing bile duct syndrome: a possible mechanism for intrahepatic cholestasis in Hodgkin’s lymphoma. Hepatology 1993; 17:70-77. Guliter S, Erdem O, Isik M, et al. Cholestatic liver disease with ductopenia (vanishing bile duct syndrome) in Hodgkin’s disease: report of a case. Tumori 2004; 90:517-520. Ozkan A, Yoruk A, Celkan T, et al. The vanishing bile duct syndrome in a child with Hodgkin disease. Med Pediatr Oncol 2001; 36:398-399. Rossini MS, Lorand-Metze I, Oliveira GB, et al. Vanishing bile duct syndrome in Hodgkin’s disease: case report. Sao Paulo Med J 2000; 118:154157. Yusuf MA, Elias E, Hubscher SG. Jaundice caused by the vanishing bile duct syndrome in a child with Hodgkin lymphoma. J Pediatr Hematol Oncol 2000; 22:154-157. De Medeiros BC, Lacerda MA, Telles JE, et al. Cholestasis secondary to Hodgkin’s disease: report of 2 cases of vanishing bile duct syndrome. Haematologica 1998; 83:1038-1040. Gottrand F, Cullu F, Mazingue F, et al. Intrahepatic cholestasis related to vanishing bile duct syndrome in Hodgkin’s disease. J Pediatr Gastroenterol Nutr 1997; 24:430-433. Marinone G, Lazzari R, Pellizzari F, et al. Acute cholestatic Hodgkin’s lymphoma: an unusual clinical picture. Haematologica 1989; 74:293-296. Crosbie OM, Crown JP, Nolan NP, et al. Resolution of paraneoplastic bile duct paucity following successful treatment of Hodgkin’s disease. Hepatology 1997; 26:5-8. Grieco Q, Miele L, Giorgi A, et al. Acute cholestatic hepatitis associated with celecoxib. Ann Pharmacother 2003; 37:748 O’Beirne JP, Cairns SR. Cholestatic hepatitis association with celecoxib. BMJ 2001; 323:23. Nachimuthu S, Volfinzon L, Gopal L. Acute hepatocellular and cholestatic injury in a patient taking celecoxib. Postgrad Med J 2001; 77:548-550. Levy C, Lindor KD. Drug-induced cholestasis. Clin Liver Dis 2003; 7:311-330. Sherlock S. The syndrome of disappearing bile ducts. Lancet 1987; 2:493496. Nakanuma Y, Tsuneyama K, Harada K. Pathology and pathogenesis of intrahepatic bile duct loss. J Hepatobiliary Pancreat Surg 2001; 8:303-315. Bendandi M, Pilei SA, Zinzani PL. Challenging paradigms in lymphoma treatment. Ann Oncol 2004; 15:703-711. Aisenberg AC. Problems in Hodgkin’s disease management. Blood 1999; 93:761-779. Horning SJ, Hoppe RT, Mason J, et al. Stanford-Kaiser Permanente G1 study for clinical stage I and IIA Hodgkin’s disease: subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation. J Clin Oncol 1997; 15:1736-1744. Press OW, LeBlanc M, Lichter AS, et al. Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and
Clinical Lymphoma & Myeloma July 2006 • 81
Cholestasis in Hodgkin’s Lymphoma
35.
36.
37. 38.
subtotal lymphoid irradiation for stage IA to IIA Hodgkin’s disease. J Clin Oncol 2001; 19:4238-4244. Specht L, Gray RG, Clarke MJ, et al. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin’s disease: a meta-analysis of 23 randomized trials involving 3,888 patients. J Clin Oncol 1998; 16:830-843. Bonfante V, Viviani S, Devizzi L. Ten years experience with ABVD plus radiotherapy: subtotal nodal (STNI) vs involved field (IFRT) in early-stage Hodgkin’s disease. Proc Amer Soc Clin Oncol 2001; 20:281a (Abstract #1120). Klasa RJ, Connors JM, Fairey R, et al. Treatment of early stage Hodgkin’s disease: improved outcome with brief chemotherapy and radiotherapy without staging laparotomy. Annal Oncol 1996; 7:S21. Tesch H, Sieber M, Ruffer JU, et al. 2 cycles of ABVD plus radiotherapy is more effective than radiotherapy alone in early stage Hodgkin’s disease - interim analysis of the HD7 trial of the GHSG. Blood 1998; 91:485a
82 • Clinical Lymphoma & Myeloma July 2006
(Abstract #2001). 39. Blay JY, Rossi JF, Wijdenes J, et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Inter J Cancer 1997; 72:424-430. 40. Seymour JF, Talpaz M, Hagemeister FB, et al. Clinical correlates of elevated serum levels of interleukin 6 in patients with untreated Hodgkin’s disease. Am J Med 1997; 102:21-28. 41. Trauner M, Fickert P, Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999; 14:946-959. 42. Reynoso-Paz S, Coppel RL, Ansari AA, et al. Vanishing bile duct syndromes: considerations of the immunobiology of autoimmune biliary diseases. Imaj 1999; 1:37-44. 43. Geubel AP, Sempoux C, Rahier J. Bile duct disorders. Clin Liver Dis 2003; 7:295-309. 44. Desmet VJ. Vanishing bile duct disorders. Prog Liver Dis 1992; 10:89121.
