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Paraneoplastic Liver Dysfunction in Prostate Cancer

2006; Elsevier BV; Volume: 32; Issue: 6 Linguagem: Inglês

10.1016/j.jpainsymman.2006.03.015

1873-6513

Sanjay Shah,

Cancer Diagnosis and Treatment

Paraneoplastic liver dysfunction is an uncommon phenomenon. It is most commonly described with renal cell carcinoma.1Chagnac A. Gal R. Kimche D. et al.Liver granulomas: a possible paraneoplastic manifestation of hypernephroma.Am J Gastroenterol. 1985; 80: 989-992PubMed Google Scholar, 2Fang J.W.S. Lau J.Y.N. Wu P.C. Lai C.L. Fulminant hepatic failure in nonmetastatic renal cell carcinoma.Dig Dis Sci. 1992; 37: 474-477Crossref PubMed Scopus (11) Google Scholar, 3Dourakis S.P. Sinani C. Deutsch M. Dimitriadou E. Hadziyannis S.J. Cholestatic jaundice as a paraneoplastic manifestation of renal cell carcinoma.Eur J Gastroenterol Hepatol. 1997; 9: 311-314Crossref PubMed Scopus (34) Google Scholar It has also been reported with soft tissue sarcoma.4Sharara A.I. Panella T.J. Fitz J.G. Paraneoplastic hepatopathy associated with soft tissue sarcoma.Gastroenterology. 1992; 103: 332Google Scholar A case of metastatic prostate cancer with symptomatic liver dysfunction of no obvious cause is described. A 64-year-old man was investigated for scrotal pain, lower backache, and raised serum levels of prostatic specific antigen (PSA) in December 2004. Clinical examination was unremarkable. Laboratory tests at the initial evaluation revealed the following: normal complete blood count, blood urea nitrogen, serum creatinine and serum electrolytes; serum PSA: 643.8 μg/L (normal <4.5); serum total bilirubin: 9 μmol/L (normal: 0–17); serum alanine transferase (ALT): 22 U/L (normal: 5–40); serum gamma-glutamyl transpeptidase (g-GT): 33 IU/L (normal: 11–50); and serum alkaline phosphatase: 86 U/L (normal: 30–120). A radioisotope bone scan showed widespread bone metastases, and the prostate biopsy demonstrated adenocarcinoma of the prostate, with a Gleason score of 4+3. As he was undergoing assessment, he became jaundiced and developed pruritus in the second week of January 2005. Liver function tests became deranged just before goserelin, a gonadorelin analog, and cyproterone (later stopped after two weeks) were started (Table 1). There was no past history of jaundice, excess alcohol use, blood transfusion, or recent travel abroad. Ultrasound of abdomen showed no liver metastases, common bile duct obstruction or intrahepepatic biliary dilatation. A few days before diagnosis, he had been taking ibuprofen, which was later changed to a diclofenac-misoprostol combination for pain in the hip. It was stopped four weeks (mid-February) after liver abnormality was first detected.Table 1Liver Function TestsaNormal values in brackets.12/30/04bInitial assessment.1/12/05cA day before initiation of anti-androgen therapy.3/14/0054/26/055/13/055/24/056/28/05Serum total bilirubin (0–17 μmol/L)9132—41290302291Serum ALT (5–40 U/L)22380—31829418875Serum g-GT (11–50 iu/L)331174—201011691025835Serum total protein (63–79 g/L)7074—72564854Serum albumin (35–50 g/L)3839—40292523Serum alkaline phosphatase (30–120 U/L)86587—939970624744Serum PSA (<4.5 μg/L)643.8956.0291.2——798.2a Normal values in brackets.b Initial assessment.c A day before initiation of anti-androgen therapy. Open table in a new tab Serum levels of PSA dropped to 291.2 μg/L two months later. However, liver dysfunction continued to remain abnormal (Table 1); platelet count dropped to 83×109/L, and activated partial thromboplastin time (APTT) test became prolonged to 37 seconds (reference range: 23–31 seconds). Clinically, jaundice deepened, and he also developed pruritus, which was severe enough to disturb his sleep and interfere with his daily activities. Other investigations, including prothrombin time and thrombin time tests were normal; and autoantibody screen (antinuclear, mitochondrial, parietal cell, smooth muscle, and liver kidney microsomal antibodies), and hepatitis B and C virus serology were negative. A repeat ultrasound of the abdomen showed no liver metastases or biliary dilatation, and the computerized tomogram (CT) of the abdomen revealed retroperitoneal, para-aortic, and left iliac lymphadenopathy, no mass lesion in the liver, and no dilatation of biliary system. There was no obvious cause for liver dysfunction in this case. Liver function tests were normal about a month before the diagnosis of prostate cancer, and were found to be abnormal a day before the patient was started on goserelin and cyproterone. Liver dysfunction worsened till his death six months later (Table 1). Although the biochemical picture was suggestive of cholestatic jaundice, no biliary obstruction was identified on ultrasound and CT scans of the abdomen. Similarly, there were no parenchymal liver metastases. Liver biopsy was considered, but the patient never seemed well enough to undergo the procedure. Goserelin and, more commonly, anti-androgen agents, such as cyproterone acetate and flutamide, have been linked to liver dysfunction.5Cetin M. Demirci D. Unal A. et al.Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma.Hum Exp Toxicol. 1999; 18: 137-140Crossref PubMed Google Scholar, 6Wysowski D.K. Fourcroy J.L. Flutamide hepatotoxicity.J Urol. 1996; 155: 209-212Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 7Lin A.D.Y. Chen K.-K. Lin A.T.L. et al.Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer.J Chin Med Assoc. 2003; 66: 735-740PubMed Google Scholar, 8http://www.yellowcard.gov.uk/dapsGoogle Scholar However, this patient was not on flutamide, and had cyproterone for only two weeks immediately after diagnosis. Additionally, liver dysfunction started before initiation of hormone therapy, and thus, did not appear to be related to hormone treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been implicated in pathogenesis of hepatotoxicity. However, NSAID-induced hepatotoxicity is rare; the incidence with ibuprofen and diclofenac is 44.6 and 39.2 per 100,000 person years, respectively.9Traversa G. Bianchi C. Da Cas R. Abraha I. Menniti-Ippolito F. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs.BMJ. 2003; 327: 18-22Crossref PubMed Scopus (169) Google Scholar Diclofenac-induced liver dysfunction usually subsides with its withdrawal,9Traversa G. Bianchi C. Da Cas R. Abraha I. Menniti-Ippolito F. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs.BMJ. 2003; 327: 18-22Crossref PubMed Scopus (169) Google Scholar, 10Bhogaraju A. Nazeer S. Al-Baghdadi Y. et al.Diclofenac-associated hepatitis.South Med J. 1999; 92: 711-713Crossref PubMed Scopus (16) Google Scholar and if it does persist, it is in the form of inactive liver disease.11Aithal P.G. Day C.P. The natural history of histologically proved drug induced liver disease.Gut. 1999; 44: 731-735Crossref PubMed Scopus (174) Google Scholar In our case, despite stopping NSAIDs, liver dysfunction continued to worsen. Cholestatic jaundice without liver metastases or biliary obstruction and dilatation has been reported with adenocarcinoma of the prostate.12Cole A. Mendlnlatt D. Aguayo J. et al.Metastatic prostate cancer (with prostate-specific antigen of 9996) presenting as obstructive jaundice.Am J Med Sci. 2000; 319: 118-122Crossref PubMed Google Scholar, 13Karakolios A. Kasapis C. Kallinikidas T. Kalpidis P. Grigoriadis N. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma.Clin Gastroenterol Hepatol. 2003; 1: 480-483Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 14Koruk M. Büyükberber M. Savas C. Kdayifci A. Paraneoplastic cholestasis associated with prostate carcinoma.Turk J Gastroenterol. 2004; 15: 53-55PubMed Google Scholar, 15Taylor J. Lindor K. Metastatic prostate cancer simulating sclerosing cholangitis.J Clin Gastroenterol. 1993; 16: 143-145Crossref PubMed Scopus (14) Google Scholar Such a cholestatic liver dysfunction improved with hormone treatment of prostate cancer and was presumed to be a paraneoplastic manifestation.12Cole A. Mendlnlatt D. Aguayo J. et al.Metastatic prostate cancer (with prostate-specific antigen of 9996) presenting as obstructive jaundice.Am J Med Sci. 2000; 319: 118-122Crossref PubMed Google Scholar, 13Karakolios A. Kasapis C. Kallinikidas T. Kalpidis P. Grigoriadis N. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma.Clin Gastroenterol Hepatol. 2003; 1: 480-483Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 14Koruk M. Büyükberber M. Savas C. Kdayifci A. Paraneoplastic cholestasis associated with prostate carcinoma.Turk J Gastroenterol. 2004; 15: 53-55PubMed Google Scholar In this case, with passage of time it appeared that biochemical abnormalities of liver dysfunction were due to a combination of predominantly hepatocellular damage and intrahepatic cholestasis. Hyperbilirubinemia and hypoalbuminemia gradually got worse; and other features of liver dysfunction, such as prolonged APTT and thrombocytopenia, developed. Serum levels of liver enzymes fell, but still remained elevated, which would suggest diminishing hepatocellular reserve. In the absence of any other identifiable cause for liver dysfunction in the current case, it appeared to be paraneoplastic and did not improve because of hormone-refractoriness of the cancer. It is a rare association of which only a few cases could be found on searching Medline and EMBASE databases.12Cole A. Mendlnlatt D. Aguayo J. et al.Metastatic prostate cancer (with prostate-specific antigen of 9996) presenting as obstructive jaundice.Am J Med Sci. 2000; 319: 118-122Crossref PubMed Google Scholar, 13Karakolios A. Kasapis C. Kallinikidas T. Kalpidis P. Grigoriadis N. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma.Clin Gastroenterol Hepatol. 2003; 1: 480-483Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 14Koruk M. Büyükberber M. Savas C. Kdayifci A. Paraneoplastic cholestasis associated with prostate carcinoma.Turk J Gastroenterol. 2004; 15: 53-55PubMed Google Scholar, 15Taylor J. Lindor K. Metastatic prostate cancer simulating sclerosing cholangitis.J Clin Gastroenterol. 1993; 16: 143-145Crossref PubMed Scopus (14) Google Scholar Pruritus can be a difficult symptom to control in patients with advanced cancer, with or without cholestasis. In this case, it did not respond to antihistamines, cholestyramine, ursodeoxycholic acid, and paroxetine,16Zylicz Z. Krajnik M. Sorge A.A.V. Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomised, controlled trial.J Pain Symptom Manage. 2003; 26: 1105-1112Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar but became bearable with ondansetron 8 mg twice a day, which was continued till death. Ondansetron has been successfully used to relieve pruritus.17Raderer M. Muller C. Scheithauer W. Ondansetron for pruritus due to cholestasis.N Engl J Med. 1994; 330: 1540Crossref PubMed Scopus (84) Google Scholar, 18Schworer H. Hartmann H. Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor agonists: effectiveness of ondansetron.Pain. 1995; 61: 33-37Abstract Full Text PDF PubMed Scopus (141) Google Scholar In summary, prostate cancer can be associated with paraneoplastic liver dysfunction. However, drugs such as anti-androgens and NSAIDs should also be considered in the differential diagnosis of unexplained jaundice in patients with metastatic prostate cancer.