- Email: [email protected]
Quiz Page September 2014
QUIZ PAGE SEPTEMBER 2014 Progressive Liver Failure Following Kidney Transplantation CLINICAL PRESENTATION
Am J Kidney Dis. 2014;64(3):xix-xxii
ANA, AMA, LKM antibody Anti–hepatitis A IgM antibody HBV surface antigen HBV viral DNA Anti-HCV antibody Anti-HIV antibody CMV plasma PCR EBV plasma PCR HSV-1 and -2 serology Rickettsia, Ehrlichia, Legionella serology Cryptococcus, Coccidioidomycosis, Lyme serology Blood and urine cultures Note: Urine drug screen also was performed and gave negative results. Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; CMV, cytomegalovirus; EBV, EpsteinBarr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgM, immunoglobulin M; LKM, liver kidney microsomal; PCR, polymerase chain reaction.
- What are the possible causes of liver
dysfunction in this immunosuppressed kidney transplant recipient? - What are the common histopathologic
features of fibrosing cholestatic hepatitis (FCH), and what are their implications? - What are the limitations of screening tests
for HBV and HCV? - What is the treatment and prognosis of
FCH?
xix
QUIZ PAGE
A 64-year-old white man with end-stage renal disease secondary to immunoglobulin A nephropathy underwent living related kidney transplantation with induction immunosuppression (antithymocyte globulin and pulsed intravenous methylprednisolone). Three months later, he presented with newonset jaundice. At this time, physical examination findings were remarkable for body mass index of 23 kg/m2, scleral icterus, absence of ascites, and without the stigmata of chronic liver disease. Laboratory tests determined levels of total bilirubin (8 mg/dL), direct bilirubin (6.4 mg/dL), aspartate aminotransferase (447 IU), alanine aminotransferase (548 IU), alkaline phosphatase (380 IU), serum albumin (3.0 g/dL), and international normalized ratio (1.2). The patient had no history of alcohol or over-the-counter drug use, and both he and his donor had no known history of liver disease or intravenous drug use. Pretransplantation serologic testing for hepatitis B virus (HBV) surface antigen, antibodies to hepatitis C virus (anti-HCV), and HIV (human immunodeficiency virus) also gave negative results for both individuals. At the time of presentation, there was no evidence of infection or autoimmune disease (Box 1). The patient’s medications included tacrolimus, mycophenolate, prednisone, valganciclovir, and sulfamethoxazole-trimethoprim. Ultrasonography of the hepatobiliary system showed mild fatty infiltration of the liver with normal liver contour, normal echogenicity, and patent hepatic vasculature. Liver biopsy showed intracanalicular cholestasis (Fig 1A) with neutrophilic cholangitis and prominent ductal reaction (Fig 1B) without viral inclusions. Four months later, repeat liver biopsy for progressive liver dysfunction showed cholestatic injury, ductal reaction, and apoptotic hepatocytes (Fig 1C) similar to the previous biopsy, with additional features of pericellular and periportal fibrosis (Fig 1D and E). Another battery of tests for signs of infection or autoimmunity gave negative results.
Box 1. List of Negative Laboratory Tests for Infection and Autoimmune Markers
QUIZ PAGE
Figure 1. Liver biopsy. (A) Cholestasis (brown material is bile) marked by black arrows; (B) ductular reaction marked by neutrophilic infiltration (yellow arrows); (C) apoptotic hepatocytes (red condensed cells; A-C: hematoxylin and eosin stain; original magnification, 340); (D) pericellular fibrosis is stained blue (Masson trichrome stain; original magnification, 340); and (E) periportal fibrosis is stained blue (Masson trichrome stain; original magnification, 310). Images courtesy of U. Ghaffar.
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Am J Kidney Dis. 2014;64(3):xix-xxii
QUIZ PAGE SEPTEMBER 2014
ANSWERS
DISCUSSION - What are the possible
causes of liver dysfunction in this immunosuppressed kidney transplant recipient? Causes of hepatitis in an immunosuppressed kidney transplant recipient include typical and atypical infections, autoimmune hepatitis, alcohol-induced liver injury, nonalcoholic steatohepatitis, and medications. Extensive testing for infection or autoimmunity gave negative results, and the patient’s medical history and clinical course were not consistent with alcoholic or nonalcoholic steatohepatitis. Sulfamethoxazole-trimethoprim and tacrolimus are well known to induce hepatotoxicity1,2; however, hepatic dysfunction persisted after the patient stopped these medications. Although tests for HBV surface antigen, anti-HCV antibodies, and cytomegalovirus DNA gave negative results on 2 separate occasions in our patient, his clinical course and liver biopsy histopathology was consistent with FCH, a rare progressive form of liver injury3 caused by HBV, HCV, and rarely by cytomegalovirus4 in an immunosuppressed state (eg, post–organ transplantation). - What are the common
histopathologic features of FCH, and what are their implications?
Am J Kidney Dis. 2014;64(3):xix-xxii
- What are the limitations
of screening tests for HBV and HCV? Our patient and donor lacked serologic evidence of HBV and HCV. However, due to the window period or other limitations, serologic tests may give falsenegative results.5 Patients with end-stage renal disease have impaired immunologic responses6 and may not mount an antibody response. Additionally, testing for HCV antibody has been shown to have lower sensitivity for identifying HCV infection in the dialysis population.7 Nucleic acid testing leads to increased sensitivity
and currently is the gold standard for diagnosis of HCV infection.5 Given the limitations of antibodybased tests, we tested for HCV RNA and detected titers greater than 69 million copies/mL, thus confirming the diagnosis. The donor subsequently was tested for HCV RNA and the result was negative. It is possible that the recipient either had asymptomatic HCV infection pretransplantation or acquired it early in the posttransplantation period. Iatrogenic immunosuppression may explain why tests for anti-HCV repeatedly gave negative results. - What is the treatment and
prognosis of FCH? Treatment of FCH following transplantation requires reducing or stopping immunosuppression therapy and treating the underlying infection. The prognosis is poor even if intensive treatment is given, and it is common for FCH to progress rapidly to hepatic failure and death.3 There have been anecdotal reports of patients with HBV-related disease showing improvement with lamivudine.8 Patients with HCVrelated disease can be treated with ribavirin and interferon,9 but ribavirin is contraindicated in patients with reduced kidney function due to the risk of hemolysis. Interferon alfa also has been associated with acute rejection and transplant loss.10 In the setting of FCH, there is a lack of data for potential benefits of novel agents against HCV, such as inhibitors of the viral protease xxi
QUIZ PAGE
As described by Xiao et al,3 the histopathologic features that characterize FCH are periportal or
pericellular/sinusoidal fibrosis, ballooning degeneration of the hepatocytes, prominent cholestasis, and variable inflammation based on host immune response. Ground-glass transformation of hepatocytes and other distinctive viral cytopathic changes may be present in FCH caused by HBV. However, inflammation may be more severe in HCV-associated FCH, the pathogenesis of which remains unclear. Unlike the damage perpetuated by chronic HBV or HCV infection, in FCH, high viral loads appear to be directly responsible for cellular degeneration or death. This process occurs relatively quickly and leads to progressive and rapid liver failure characterized by widespread degeneration of hepatocytes, fibrosis, and compromise of bile acid transporter proteins leading to cholestasis.
or the viral polymerase known as NS5B (nonstructural protein 5B). The immunosuppression was reduced in our patient, but he died of complications of fulminant liver failure soon after the diagnosis was made.
FINAL DIAGNOSIS Fibrosing cholestatic hepatitis secondary to HCV infection.
ACKNOWLEDGEMENTS We thank Dr Umbar Ghaffar from the University of Arkansas for Medical Sciences for obtaining liver biopsy pictures.
REFERENCES
QUIZ PAGE
1. Zaman F, Ye G, Abreo KD, Latif S, Zibari GB. Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure. Clin Transplant. 2003;17(5):461-464. 2. Yadav DK, Gera DN, Gumber MR, et al. Tacrolimusinduced severe cholestasis complicating renal transplantation. Ren Fail. 2013;35:735-737. 3. Xiao SY, Lu L, Wang HL. Fibrosing cholestatic hepatitis: clinicopathologic spectrum, diagnosis and
xxii
pathogenesis. Int J Clin Exp Pathol. 2008;1(5):396-402. 4. Agarwal SK, Kalra V, Dinda A, et al. Fibrosing cholestatic hepatitis in renal transplant recipient with CMV infection: a case report. Int Urol Nephrol. 2004;36(3):433-435. 5. Pereira BJ, Levey AS. Hepatitis C virus infection in dialysis and renal transplantation. Kidney Int. 1997;51(4): 981-999. 6. Girndt M, Sester U, Sester M, et al. Impaired cellular immunity in patients with end-stage renal failure. Nephrol Dial Transplant. 2000;14: 2807-2810. 7. Kalantar-Zadeh K, Miller LG, Daar ES. Diagnostic discordance for hepatitis C virus infection in hemodialysis patients. Am J Kidney Dis. 2005;46(2):290. 8. Chan TM, Wu PC, Li FK, Lai CL, Cheng IK, Lai KN. Treatment of fibrosing cholestatic hepatitis with lamivudine. Gastroenterology. 1998;115:177-181. 9. Taniguchi M, Furukawa H, Shimamura T, et al. Impact of double-filtration plasmapheresis in combination with interferon and ribavirin in living donor liver transplant recipients with hepatitis C. Transplantation. 2006;81:1747-1749.
10. Sharma RK, Bansal SB, Gupta A, Gulati S, Kumar A, Prasad N. Chronic hepatitis C virus infection in renal transplant: treatment and outcome. Clin Transplant. 2006;20(6):677-683. CASE PROVIDED AND AUTHORED BY Nitin Relia, MD,1 Chhavi Kaushik, MD,2 Fnu Shailesh, MD,3 and Sundararaman Swaminathan, MD,4 1Division of Nephrology, Northwestern University, Chicago, IL; Divisions of 2 Radiology and 3Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR; and 4Division of Nephrology, University of Virginia School of Medicine, Charlottesville, VA. Address correspondence to Fnu Shailesh, MD, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205-7199. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014. 02.031 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2014;64(3):xix-xxii
Am J Kidney Dis. 2014;64(3):xix-xxii
ANA, AMA, LKM antibody Anti–hepatitis A IgM antibody HBV surface antigen HBV viral DNA Anti-HCV antibody Anti-HIV antibody CMV plasma PCR EBV plasma PCR HSV-1 and -2 serology Rickettsia, Ehrlichia, Legionella serology Cryptococcus, Coccidioidomycosis, Lyme serology Blood and urine cultures Note: Urine drug screen also was performed and gave negative results. Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; CMV, cytomegalovirus; EBV, EpsteinBarr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgM, immunoglobulin M; LKM, liver kidney microsomal; PCR, polymerase chain reaction.
- What are the possible causes of liver
dysfunction in this immunosuppressed kidney transplant recipient? - What are the common histopathologic
features of fibrosing cholestatic hepatitis (FCH), and what are their implications? - What are the limitations of screening tests
for HBV and HCV? - What is the treatment and prognosis of
FCH?
xix
QUIZ PAGE
A 64-year-old white man with end-stage renal disease secondary to immunoglobulin A nephropathy underwent living related kidney transplantation with induction immunosuppression (antithymocyte globulin and pulsed intravenous methylprednisolone). Three months later, he presented with newonset jaundice. At this time, physical examination findings were remarkable for body mass index of 23 kg/m2, scleral icterus, absence of ascites, and without the stigmata of chronic liver disease. Laboratory tests determined levels of total bilirubin (8 mg/dL), direct bilirubin (6.4 mg/dL), aspartate aminotransferase (447 IU), alanine aminotransferase (548 IU), alkaline phosphatase (380 IU), serum albumin (3.0 g/dL), and international normalized ratio (1.2). The patient had no history of alcohol or over-the-counter drug use, and both he and his donor had no known history of liver disease or intravenous drug use. Pretransplantation serologic testing for hepatitis B virus (HBV) surface antigen, antibodies to hepatitis C virus (anti-HCV), and HIV (human immunodeficiency virus) also gave negative results for both individuals. At the time of presentation, there was no evidence of infection or autoimmune disease (Box 1). The patient’s medications included tacrolimus, mycophenolate, prednisone, valganciclovir, and sulfamethoxazole-trimethoprim. Ultrasonography of the hepatobiliary system showed mild fatty infiltration of the liver with normal liver contour, normal echogenicity, and patent hepatic vasculature. Liver biopsy showed intracanalicular cholestasis (Fig 1A) with neutrophilic cholangitis and prominent ductal reaction (Fig 1B) without viral inclusions. Four months later, repeat liver biopsy for progressive liver dysfunction showed cholestatic injury, ductal reaction, and apoptotic hepatocytes (Fig 1C) similar to the previous biopsy, with additional features of pericellular and periportal fibrosis (Fig 1D and E). Another battery of tests for signs of infection or autoimmunity gave negative results.
Box 1. List of Negative Laboratory Tests for Infection and Autoimmune Markers
QUIZ PAGE
Figure 1. Liver biopsy. (A) Cholestasis (brown material is bile) marked by black arrows; (B) ductular reaction marked by neutrophilic infiltration (yellow arrows); (C) apoptotic hepatocytes (red condensed cells; A-C: hematoxylin and eosin stain; original magnification, 340); (D) pericellular fibrosis is stained blue (Masson trichrome stain; original magnification, 340); and (E) periportal fibrosis is stained blue (Masson trichrome stain; original magnification, 310). Images courtesy of U. Ghaffar.
xx
Am J Kidney Dis. 2014;64(3):xix-xxii
QUIZ PAGE SEPTEMBER 2014
ANSWERS
DISCUSSION - What are the possible
causes of liver dysfunction in this immunosuppressed kidney transplant recipient? Causes of hepatitis in an immunosuppressed kidney transplant recipient include typical and atypical infections, autoimmune hepatitis, alcohol-induced liver injury, nonalcoholic steatohepatitis, and medications. Extensive testing for infection or autoimmunity gave negative results, and the patient’s medical history and clinical course were not consistent with alcoholic or nonalcoholic steatohepatitis. Sulfamethoxazole-trimethoprim and tacrolimus are well known to induce hepatotoxicity1,2; however, hepatic dysfunction persisted after the patient stopped these medications. Although tests for HBV surface antigen, anti-HCV antibodies, and cytomegalovirus DNA gave negative results on 2 separate occasions in our patient, his clinical course and liver biopsy histopathology was consistent with FCH, a rare progressive form of liver injury3 caused by HBV, HCV, and rarely by cytomegalovirus4 in an immunosuppressed state (eg, post–organ transplantation). - What are the common
histopathologic features of FCH, and what are their implications?
Am J Kidney Dis. 2014;64(3):xix-xxii
- What are the limitations
of screening tests for HBV and HCV? Our patient and donor lacked serologic evidence of HBV and HCV. However, due to the window period or other limitations, serologic tests may give falsenegative results.5 Patients with end-stage renal disease have impaired immunologic responses6 and may not mount an antibody response. Additionally, testing for HCV antibody has been shown to have lower sensitivity for identifying HCV infection in the dialysis population.7 Nucleic acid testing leads to increased sensitivity
and currently is the gold standard for diagnosis of HCV infection.5 Given the limitations of antibodybased tests, we tested for HCV RNA and detected titers greater than 69 million copies/mL, thus confirming the diagnosis. The donor subsequently was tested for HCV RNA and the result was negative. It is possible that the recipient either had asymptomatic HCV infection pretransplantation or acquired it early in the posttransplantation period. Iatrogenic immunosuppression may explain why tests for anti-HCV repeatedly gave negative results. - What is the treatment and
prognosis of FCH? Treatment of FCH following transplantation requires reducing or stopping immunosuppression therapy and treating the underlying infection. The prognosis is poor even if intensive treatment is given, and it is common for FCH to progress rapidly to hepatic failure and death.3 There have been anecdotal reports of patients with HBV-related disease showing improvement with lamivudine.8 Patients with HCVrelated disease can be treated with ribavirin and interferon,9 but ribavirin is contraindicated in patients with reduced kidney function due to the risk of hemolysis. Interferon alfa also has been associated with acute rejection and transplant loss.10 In the setting of FCH, there is a lack of data for potential benefits of novel agents against HCV, such as inhibitors of the viral protease xxi
QUIZ PAGE
As described by Xiao et al,3 the histopathologic features that characterize FCH are periportal or
pericellular/sinusoidal fibrosis, ballooning degeneration of the hepatocytes, prominent cholestasis, and variable inflammation based on host immune response. Ground-glass transformation of hepatocytes and other distinctive viral cytopathic changes may be present in FCH caused by HBV. However, inflammation may be more severe in HCV-associated FCH, the pathogenesis of which remains unclear. Unlike the damage perpetuated by chronic HBV or HCV infection, in FCH, high viral loads appear to be directly responsible for cellular degeneration or death. This process occurs relatively quickly and leads to progressive and rapid liver failure characterized by widespread degeneration of hepatocytes, fibrosis, and compromise of bile acid transporter proteins leading to cholestasis.
or the viral polymerase known as NS5B (nonstructural protein 5B). The immunosuppression was reduced in our patient, but he died of complications of fulminant liver failure soon after the diagnosis was made.
FINAL DIAGNOSIS Fibrosing cholestatic hepatitis secondary to HCV infection.
ACKNOWLEDGEMENTS We thank Dr Umbar Ghaffar from the University of Arkansas for Medical Sciences for obtaining liver biopsy pictures.
REFERENCES
QUIZ PAGE
1. Zaman F, Ye G, Abreo KD, Latif S, Zibari GB. Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure. Clin Transplant. 2003;17(5):461-464. 2. Yadav DK, Gera DN, Gumber MR, et al. Tacrolimusinduced severe cholestasis complicating renal transplantation. Ren Fail. 2013;35:735-737. 3. Xiao SY, Lu L, Wang HL. Fibrosing cholestatic hepatitis: clinicopathologic spectrum, diagnosis and
xxii
pathogenesis. Int J Clin Exp Pathol. 2008;1(5):396-402. 4. Agarwal SK, Kalra V, Dinda A, et al. Fibrosing cholestatic hepatitis in renal transplant recipient with CMV infection: a case report. Int Urol Nephrol. 2004;36(3):433-435. 5. Pereira BJ, Levey AS. Hepatitis C virus infection in dialysis and renal transplantation. Kidney Int. 1997;51(4): 981-999. 6. Girndt M, Sester U, Sester M, et al. Impaired cellular immunity in patients with end-stage renal failure. Nephrol Dial Transplant. 2000;14: 2807-2810. 7. Kalantar-Zadeh K, Miller LG, Daar ES. Diagnostic discordance for hepatitis C virus infection in hemodialysis patients. Am J Kidney Dis. 2005;46(2):290. 8. Chan TM, Wu PC, Li FK, Lai CL, Cheng IK, Lai KN. Treatment of fibrosing cholestatic hepatitis with lamivudine. Gastroenterology. 1998;115:177-181. 9. Taniguchi M, Furukawa H, Shimamura T, et al. Impact of double-filtration plasmapheresis in combination with interferon and ribavirin in living donor liver transplant recipients with hepatitis C. Transplantation. 2006;81:1747-1749.
10. Sharma RK, Bansal SB, Gupta A, Gulati S, Kumar A, Prasad N. Chronic hepatitis C virus infection in renal transplant: treatment and outcome. Clin Transplant. 2006;20(6):677-683. CASE PROVIDED AND AUTHORED BY Nitin Relia, MD,1 Chhavi Kaushik, MD,2 Fnu Shailesh, MD,3 and Sundararaman Swaminathan, MD,4 1Division of Nephrology, Northwestern University, Chicago, IL; Divisions of 2 Radiology and 3Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR; and 4Division of Nephrology, University of Virginia School of Medicine, Charlottesville, VA. Address correspondence to Fnu Shailesh, MD, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205-7199. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014. 02.031 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2014;64(3):xix-xxii