- Email: [email protected]
Liver cirrhosis and membranoproliferative glomerulonephritis caused by inapparent hepatitis C virus infection
ARTICLE IN PRESS
Pathology – Research and Practice 202 (2006) 891–894 www.elsevier.de/prp
TEACHING CASE
Liver cirrhosis and membranoproliferative glomerulonephritis caused by inapparent hepatitis C virus infection Thomas Kalinskia,, Thomas Klanteb, Ilona Pa¨gec, Regine Schneider-Stocka, Frank Dombrowskia, Albert Roessnera a
Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany Department of Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany c Department of Clinical Chemistry, Otto-von-Guericke-University, Magdeburg, Germany b
Received 13 September 2006; accepted 18 October 2006
Abstract We report on an autopsy case of a 44-year-old woman who died of combined hepatic and renal failure and bacterial infection. Postmortem examination revealed advanced liver cirrhosis and membranoproliferative glomerulonephritis (MPGN), caused by clinically inapparent hepatitis C virus (HCV) infection. The diagnosis was confirmed by reverse transcription polymerase chain reaction (RT-PCR) of HCV RNA in formalin-fixed, paraffin-embedded (FFPE) liver tissue. We conclude that liver cirrhosis and concomitant MPGN should arouse suspicion of HCV infection despite ambiguous or negative results from serological analyses. Specimens of FFPE liver tissue may be used for the diagnosis of HCV infection, even if the tissue was obtained in a postmortem examination. r 2006 Elsevier GmbH. All rights reserved. Keywords: Hepatitis C virus infection; Liver cirrhosis; Membranoproliferative glomerulonephritis
Introduction Hepatitis C virus (HCV) infection is a significant cause of chronic hepatitis. Liver cirrhosis is a severe complication and may occur in about 20% of cases with chronic HCV infection. Besides a certain HCV genotype, alcohol consumption has been found to be associated with a higher risk of progression to cirrhosis in patients with HCV infection [1,5]. Liver failure may be a cause of death in advanced disease. Interferon treatment with or without ribavirin can provide an effective therapy in some cases of chronic HCV infection [8]. The diagnosis depends on the detection of elevated aminotransferase levels, anti-HCV antibodies, and HCV Corresponding author. Tel.: +49 391 6717874; fax: +49 391 67290724. E-mail address: [email protected] (T. Kalinski).
0344-0338/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2006.10.001
RNA in blood samples. However, there are situations in which laboratory analyses provide ambiguous or negative results, despite an ongoing HCV infection [9]. In this report, we present a case of end-stage liver cirrhosis caused by clinically inapparent HCV infection with concomitant membranoproliferative glomerulonephritis (MPGN), representing a severe complication in chronic HCV infection.
Case report A 44-year-old female patient died shortly after admission to the intensive care unit of Magdeburg University Medical Center. The patient was suffering from hepatic and renal failure with general edema, including lung edema and ascites, and encephalopathy.
ARTICLE IN PRESS 892
T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
Mechanical respiration was inevitable and had been started in a general hospital 1 day before admission. A central venous catheter was also applied. In addition, signs of acute bacterial infection were apparent. Clinical examination at admission further revealed jaundice and peripheral cyanosis. The patient was conscious but disorientated. Liver cirrhosis and splenomegaly were palpable. Abdominal ultrasound sonography revealed enlarged liver with knotty margins and signal enhancement, inconspicuous pancreas, and enlarged spleen. Hepatic failure was consistent with high ammonine (182.8 mmol/l), elevated liver enzymes (aspartate aminotransferase: 2.89 mmol/s l, alanine aminotransferase: 0.76 mmol/s l, lactate dehydrogenase: 10.49 mmol/s l, g-glutamyl transpeptidase: 1.99 mmol/s l), low albumin (9.8 g/l), and shortened Quick’s time (25%). Renal failure was indicated by highly elevated creatinine
(464 mmol/l) and hyperpotassemia (6.17 mmol/l). Massive leucocytosis (67.1 Gpt/l) and high C-reactive protein (197.4 mg/l) expressed acute bacterial infection. Hypoglycemia (0.82 mmol/l) was noticed. Hepatitis B surface antigen or anti-HCV antibodies were not detected. The patient was treated with hemodialysis and balanced hydration. Further medical treatment included intravenous administration of glucose, sedation with midazolam and fentanyl, and antiobiosis with vancomycin and meropenem. Ursodeoxycholic acid, lactulose, furosemide, spironolactone, and phytomenadione were administered per stomach tube. Due to persistent low blood pressure, intravenous administration of catecholamines and hydrocortisone was necessary. Acidosis was buffered with sodium bicarbonate. However, cardiopulmonary function deteriorated. Despite final high doses of catecholamines, cardiovascular
Fig. 1. Histopathological findings. (A) Nodular liver cirrhosis with interconnecting fibrous scars, azan. (B) Centrolobular fibrosis, fatty change, and lymphocytic infiltration of liver parenchyma, hematoxylin–eosin. (C) Reactive bile duct proliferations, anticytokeratin 7. (D) Concomitant detection of Mallory’s hyalin in hepatocytes, anti-ubiquitin. (E) Enlarged glomerulum with mesangial cell proliferation, hematoxylin–eosin. (F) Glomerulum with subendothelial and mesangial protein deposits, acid fuchsinorange G. (G) Subendothelial protein deposits (arrows), semithin section stained according to Richardson. (H) Myocardium with abscess, hematoxylin–eosin. (I) Colonization of myocardial abscess with Gram-positive cocci, Gram.
ARTICLE IN PRESS T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
function was not sustainable, and the patient died of circulatory shock. Microbiological analyses of peripheral blood, taken before administration of antibiosis, later revealed staphylococcus aureus infection. Regarding the patient’s history, a histologically confirmed diagnosis of liver cirrhosis has been known for 7 years. Repeated blood analyses during this time did not give evidence of hepatitis B virus or HCV infection. As elevated levels of antimitochondrial antibodies were detected, primary biliary cirrhosis (PBC) was proposed. However, the histopathological findings were not typical, and therefore, the reason for the cirrhosis remained cryptogenic. Postmortem examination of the patient confirmed advanced liver cirrhosis (Fig. 1A). Fatty change and lymphocytic infiltration of the liver parenchyma were apparent (Fig. 1B), and so were reactive bile duct proliferations (Fig. 1C). Mallory’s hyalin in hepatocytes was detected focally (Fig. 1D). The histological findings of the kidneys were consistent with MPGN type I. Enlarged glomerula with mesangial cell proliferations (Fig. 1E) as well as subendothelial and mesangial protein deposits were identified (Figs. 1F, G). Abscessing inflammation colonized with Gram-positive cocci was detected in the myocardium (Fig. 1H, I). Morphological signs of acute cardiopulmonary failure were present. As the constellation of MPGN and concomitant liver cirrhosis aroused suspicion of HCV infection, we further performed molecular analyses on formalin-fixed, paraffin-embedded (FFPE) liver specimens. RNA extraction, reverse transcription, and PCR were carried out as described previously [9]. Briefly, total RNA was prepared from four 10 mm-thick slices of FFPE liver tissue according to the manufacturer’s protocol (Ambion, Austin, USA). For HCV detection, nested PCR was performed using 0.15 ml Taq DNA polymerase (Invitrogen, Carlsbad, USA) in the presence of 1.5 ml MgCl2 (50 mM, Invitrogen), 2.5 ml PCR buffer (Invitrogen), 2 ml dNTPs (10 pmol), 1.25 ml of each primer (12.5 pmol), and 5 ml cDNA. A second PCR was run
Fig. 2. Detection of HCV RNA in formalin-fixed, paraffinembedded liver tissue visualized on a 9% acrylamide gel (assembled from the original gel images).
893
with 1 ml of the original PCR product, 1:10, and 1:100 dilution, respectively. HCV primers were used for the first PCR run: sense 50 -CTGTGAGGAACTAC TGTCTT-30 and antisense 50 -AACACTACTCGGC TAGCAGT-30 (221 bp), and for the second PCR run 50 -TTCACGCAGAAAGCGTCTAG-30 and antisense 50 -GTTGATCCAAGAAAGGACCC-30 (145 bp). Prior to HCV PCR, ß2-microglobulin was successfully amplified to confirm adequate RNA quality. The results of HCV PCRs are shown in Fig. 2. The first and second run of HCV PCRs revealed positive results. Negative second PCR using 1:100 dilution indicated low copy numbers. Additionally included positive and negative controls yielded the expected results.
Discussion Liver cirrhosis is the final stage of many chronic liver diseases, including alcoholic, infectious, circulatory, toxic, metabolic, and inherited disorders. When all these causes are excluded, cases with obscure origin remain and are designated as cryptogenic cirrhosis. The diagnosis depends on proper anamnestic information, clinical and laboratory examinations, and morphological evaluation of liver biopsies. The differential diagnosis may be difficult in cases with overlapping symptoms of more than one underlying disorder causing cirrhosis. Diagnostic problems may also arise from false-positive or false-negative results of the laboratory examinations. The latter was the diagnostic pitfall in the case reported here. In the patient’s history, repeated false-negative serological examinations of HCV infection gave no evidence of anti-HCV immunoreaction, and no HCV-RNA positivity was reported. The diagnosis of primary biliary cirrhosis has been assumed in between on account of a false-positive test, indicating an elevated titer of antimitochondrial antibodies. Among other disorders, chronic HCV infection has been regarded as a potential cause of liver cirrhosis by a pathologist evaluating a patient’s liver biopsy. Although the typical morphological signs of HCV infection are well defined [7], the differential diagnosis in advanced liver cirrhosis may be difficult. As in this case report, parenchymal steatosis can be associated with chronic HCV infection or with alcoholic liver disease. Also, Mallory’s hyalin is frequently found in alcoholic liver disease, but may also be detected in HCV patients [7]. However, both findings can be observed in metabolic disorders such as Wilson’s disease [3]. In PBC, lymphocytic infiltrations may resemble chronic HCV infection. Reactive bile duct proliferations, too, may be present in hepatic diseases other than PBC. Therefore, in the case reported here, it was impossible to clarify the etiology of liver cirrhosis without a doubt. Besides HCV infection, alcoholic liver disease and PBC could not be
ARTICLE IN PRESS 894
T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
excluded. It is rather the total of findings which would have given a clue to the diagnosis. In this regard, renal failure was a significant finding. Although MPGN was diagnosed only after postmortem examination, a correlation between HCV infection and MPGN is known from the literature [2,4,6]. A prevalence of 60% for HCV infection in MPGN has previously been reported from Japan [10]. The pathogenesis of MPGN in HCV infection has been associated with a deposition of immune complexes containing hepatitis C antibodies, hepatitis C antigens, and complement, independent of the presence or absence of HCV-associated cryoglobulinemia [4]. However, acute renal failure is an expectable and severe complication in patients with advanced liver cirrhosis and ascites, known as hepatorenal syndrome. In contrast to MPGN, the morphology of renal biopsies in hepatorenal syndrome would be normal. One might speculate that a renal biopsy would have helped in finding the diagnosis in the case reported here. However, the prognosis was poor, since the liver cirrhosis had already been at an advanced stage. Nevertheless, if renal failure occurs concomitantly with liver cirrhosis, HCV infection should be considered, even if serological examinations fail to detect anti-HCV antibodies. In such cases, the molecular-genetic detection of HCV RNA by PCR is obviously inevitable. Besides HCV-RNA detection in blood samples, its detection in FFPE archival liver tissue has been shown to be a practicable method, even if specimens obtained by thin-needle biopsy are used [7]. In the present case, we applied this method to FFPE liver tissue obtained in a postmortem examination. Although there was an autolysis time of 1 day after death, HCV RNA was still detectable, and the cause of liver cirrhosis and concomitant MPGN was clearly identified. Therefore, we recommend this method for the detection of HCV infection in FFPE liver biopsies of similar cases in which blood analyses were not carried out or provided ambiguous or negative results. An early detection of HCV infection may lead to a favorable course of the disease if there is a response to therapy. Apart from hepatic and renal failure due to liver cirrhosis and MPGN, a staphylococcus aureus infection with abscesses in the myocardium was a severe complication in the case presented here. The circulatory shock, which was the cause of death, may be attributed to one of these disorders or to the combination of them.
We conclude that the diagnosis of HCV infection in cases of liver cirrhosis may require a molecular-genetic analysis. Concomitant MPGN should arouse suspicion of HCV infection. Specimens of FFPE liver tissue can be used for the detection of HCV RNA, even if the tissue was obtained in a postmortem examination.
References [1] S. Bellentani, G. Pozzato, G. Saccoccio, M. Crovatto, L.S. Croce, L. Mazzoran, F. Masutti, G. Cristianini, C. Tiribelli, Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study, Gut 44 (1999) 874–880. [2] D.M. Burstein, R.A. Rodby, Membranoproliferative glomerulonephritis associated with hepatitis C virus infection, J. Am. Soc. Nephrol. 4 (1993) 1288–1293. [3] R.S. Cotran, V. Kumar, S.L. Robbins, Cirrhosis of Wilson’s disease, in: R.S. Cotran, V. Kumar, S.L. Robbins (Eds.), Robbins Pathologic Basis of Disease, W.B. Saunders, Philadelphia, 1989, pp. 956–957. [4] L. Daghestani, C. Pomeroy, Renal manifestations of hepatitis C infection, Am. J. Med. 106 (1999) 347–354. [5] M. Danta, G.J. Dore, L. Hennessy, Y. Li, C.R. Vickers, H. Harley, M. Ngu, W. Reed, P.V. Desmond, W. Sievert, G.C. Farrell, J.M. Kaldor, R.G. Batey, Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection, Med. J. Aust. 177 (2002) 240–245. [6] R. Davda, J. Peterson, R. Weiner, B. Croker, J.Y. Lau, Membranous glomerulonephritis in association with hepatitis C virus infection, Am. J. Kidney Dis. 22 (1993) 452–455. [7] H.P. Fischer, E. Willsch, E. Bierhoff, U. Pfeifer, Histopathologic findings in chronic hepatitis C, J. Hepatol. 24 (1996) 35–42. [8] D.B. Strader, T. Wright, D.L. Thomas, L.B. Seeff; American Association for the Study of Liver Diseases, Diagnosis, management, and treatment of hepatitis C, Hepatology 39 (2004) 1147–1171. [9] S. Vogt, R. Schneider-Stock, S. Klauck, A. Roessner, C. Rocken, Detection of hepatitis C virus RNA in formalinfixed, paraffin-embedded thin-needle liver biopsy specimens, Am. J. Clin. Pathol. 120 (2003) 536–543. [10] H. Yamabe, R.J. Johnson, D.R. Gretch, K. Fukushi, H. Osawa, M. Miyata, H. Inuma, T. Sasaki, M. Kaizuka, N. Tamura, S. Tsunoda, Y. Fujita, K. Onodera, Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan, J. Am. Soc. Nephrol. 6 (1995) 220–223.
Pathology – Research and Practice 202 (2006) 891–894 www.elsevier.de/prp
TEACHING CASE
Liver cirrhosis and membranoproliferative glomerulonephritis caused by inapparent hepatitis C virus infection Thomas Kalinskia,, Thomas Klanteb, Ilona Pa¨gec, Regine Schneider-Stocka, Frank Dombrowskia, Albert Roessnera a
Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany Department of Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany c Department of Clinical Chemistry, Otto-von-Guericke-University, Magdeburg, Germany b
Received 13 September 2006; accepted 18 October 2006
Abstract We report on an autopsy case of a 44-year-old woman who died of combined hepatic and renal failure and bacterial infection. Postmortem examination revealed advanced liver cirrhosis and membranoproliferative glomerulonephritis (MPGN), caused by clinically inapparent hepatitis C virus (HCV) infection. The diagnosis was confirmed by reverse transcription polymerase chain reaction (RT-PCR) of HCV RNA in formalin-fixed, paraffin-embedded (FFPE) liver tissue. We conclude that liver cirrhosis and concomitant MPGN should arouse suspicion of HCV infection despite ambiguous or negative results from serological analyses. Specimens of FFPE liver tissue may be used for the diagnosis of HCV infection, even if the tissue was obtained in a postmortem examination. r 2006 Elsevier GmbH. All rights reserved. Keywords: Hepatitis C virus infection; Liver cirrhosis; Membranoproliferative glomerulonephritis
Introduction Hepatitis C virus (HCV) infection is a significant cause of chronic hepatitis. Liver cirrhosis is a severe complication and may occur in about 20% of cases with chronic HCV infection. Besides a certain HCV genotype, alcohol consumption has been found to be associated with a higher risk of progression to cirrhosis in patients with HCV infection [1,5]. Liver failure may be a cause of death in advanced disease. Interferon treatment with or without ribavirin can provide an effective therapy in some cases of chronic HCV infection [8]. The diagnosis depends on the detection of elevated aminotransferase levels, anti-HCV antibodies, and HCV Corresponding author. Tel.: +49 391 6717874; fax: +49 391 67290724. E-mail address: [email protected] (T. Kalinski).
0344-0338/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2006.10.001
RNA in blood samples. However, there are situations in which laboratory analyses provide ambiguous or negative results, despite an ongoing HCV infection [9]. In this report, we present a case of end-stage liver cirrhosis caused by clinically inapparent HCV infection with concomitant membranoproliferative glomerulonephritis (MPGN), representing a severe complication in chronic HCV infection.
Case report A 44-year-old female patient died shortly after admission to the intensive care unit of Magdeburg University Medical Center. The patient was suffering from hepatic and renal failure with general edema, including lung edema and ascites, and encephalopathy.
ARTICLE IN PRESS 892
T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
Mechanical respiration was inevitable and had been started in a general hospital 1 day before admission. A central venous catheter was also applied. In addition, signs of acute bacterial infection were apparent. Clinical examination at admission further revealed jaundice and peripheral cyanosis. The patient was conscious but disorientated. Liver cirrhosis and splenomegaly were palpable. Abdominal ultrasound sonography revealed enlarged liver with knotty margins and signal enhancement, inconspicuous pancreas, and enlarged spleen. Hepatic failure was consistent with high ammonine (182.8 mmol/l), elevated liver enzymes (aspartate aminotransferase: 2.89 mmol/s l, alanine aminotransferase: 0.76 mmol/s l, lactate dehydrogenase: 10.49 mmol/s l, g-glutamyl transpeptidase: 1.99 mmol/s l), low albumin (9.8 g/l), and shortened Quick’s time (25%). Renal failure was indicated by highly elevated creatinine
(464 mmol/l) and hyperpotassemia (6.17 mmol/l). Massive leucocytosis (67.1 Gpt/l) and high C-reactive protein (197.4 mg/l) expressed acute bacterial infection. Hypoglycemia (0.82 mmol/l) was noticed. Hepatitis B surface antigen or anti-HCV antibodies were not detected. The patient was treated with hemodialysis and balanced hydration. Further medical treatment included intravenous administration of glucose, sedation with midazolam and fentanyl, and antiobiosis with vancomycin and meropenem. Ursodeoxycholic acid, lactulose, furosemide, spironolactone, and phytomenadione were administered per stomach tube. Due to persistent low blood pressure, intravenous administration of catecholamines and hydrocortisone was necessary. Acidosis was buffered with sodium bicarbonate. However, cardiopulmonary function deteriorated. Despite final high doses of catecholamines, cardiovascular
Fig. 1. Histopathological findings. (A) Nodular liver cirrhosis with interconnecting fibrous scars, azan. (B) Centrolobular fibrosis, fatty change, and lymphocytic infiltration of liver parenchyma, hematoxylin–eosin. (C) Reactive bile duct proliferations, anticytokeratin 7. (D) Concomitant detection of Mallory’s hyalin in hepatocytes, anti-ubiquitin. (E) Enlarged glomerulum with mesangial cell proliferation, hematoxylin–eosin. (F) Glomerulum with subendothelial and mesangial protein deposits, acid fuchsinorange G. (G) Subendothelial protein deposits (arrows), semithin section stained according to Richardson. (H) Myocardium with abscess, hematoxylin–eosin. (I) Colonization of myocardial abscess with Gram-positive cocci, Gram.
ARTICLE IN PRESS T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
function was not sustainable, and the patient died of circulatory shock. Microbiological analyses of peripheral blood, taken before administration of antibiosis, later revealed staphylococcus aureus infection. Regarding the patient’s history, a histologically confirmed diagnosis of liver cirrhosis has been known for 7 years. Repeated blood analyses during this time did not give evidence of hepatitis B virus or HCV infection. As elevated levels of antimitochondrial antibodies were detected, primary biliary cirrhosis (PBC) was proposed. However, the histopathological findings were not typical, and therefore, the reason for the cirrhosis remained cryptogenic. Postmortem examination of the patient confirmed advanced liver cirrhosis (Fig. 1A). Fatty change and lymphocytic infiltration of the liver parenchyma were apparent (Fig. 1B), and so were reactive bile duct proliferations (Fig. 1C). Mallory’s hyalin in hepatocytes was detected focally (Fig. 1D). The histological findings of the kidneys were consistent with MPGN type I. Enlarged glomerula with mesangial cell proliferations (Fig. 1E) as well as subendothelial and mesangial protein deposits were identified (Figs. 1F, G). Abscessing inflammation colonized with Gram-positive cocci was detected in the myocardium (Fig. 1H, I). Morphological signs of acute cardiopulmonary failure were present. As the constellation of MPGN and concomitant liver cirrhosis aroused suspicion of HCV infection, we further performed molecular analyses on formalin-fixed, paraffin-embedded (FFPE) liver specimens. RNA extraction, reverse transcription, and PCR were carried out as described previously [9]. Briefly, total RNA was prepared from four 10 mm-thick slices of FFPE liver tissue according to the manufacturer’s protocol (Ambion, Austin, USA). For HCV detection, nested PCR was performed using 0.15 ml Taq DNA polymerase (Invitrogen, Carlsbad, USA) in the presence of 1.5 ml MgCl2 (50 mM, Invitrogen), 2.5 ml PCR buffer (Invitrogen), 2 ml dNTPs (10 pmol), 1.25 ml of each primer (12.5 pmol), and 5 ml cDNA. A second PCR was run
Fig. 2. Detection of HCV RNA in formalin-fixed, paraffinembedded liver tissue visualized on a 9% acrylamide gel (assembled from the original gel images).
893
with 1 ml of the original PCR product, 1:10, and 1:100 dilution, respectively. HCV primers were used for the first PCR run: sense 50 -CTGTGAGGAACTAC TGTCTT-30 and antisense 50 -AACACTACTCGGC TAGCAGT-30 (221 bp), and for the second PCR run 50 -TTCACGCAGAAAGCGTCTAG-30 and antisense 50 -GTTGATCCAAGAAAGGACCC-30 (145 bp). Prior to HCV PCR, ß2-microglobulin was successfully amplified to confirm adequate RNA quality. The results of HCV PCRs are shown in Fig. 2. The first and second run of HCV PCRs revealed positive results. Negative second PCR using 1:100 dilution indicated low copy numbers. Additionally included positive and negative controls yielded the expected results.
Discussion Liver cirrhosis is the final stage of many chronic liver diseases, including alcoholic, infectious, circulatory, toxic, metabolic, and inherited disorders. When all these causes are excluded, cases with obscure origin remain and are designated as cryptogenic cirrhosis. The diagnosis depends on proper anamnestic information, clinical and laboratory examinations, and morphological evaluation of liver biopsies. The differential diagnosis may be difficult in cases with overlapping symptoms of more than one underlying disorder causing cirrhosis. Diagnostic problems may also arise from false-positive or false-negative results of the laboratory examinations. The latter was the diagnostic pitfall in the case reported here. In the patient’s history, repeated false-negative serological examinations of HCV infection gave no evidence of anti-HCV immunoreaction, and no HCV-RNA positivity was reported. The diagnosis of primary biliary cirrhosis has been assumed in between on account of a false-positive test, indicating an elevated titer of antimitochondrial antibodies. Among other disorders, chronic HCV infection has been regarded as a potential cause of liver cirrhosis by a pathologist evaluating a patient’s liver biopsy. Although the typical morphological signs of HCV infection are well defined [7], the differential diagnosis in advanced liver cirrhosis may be difficult. As in this case report, parenchymal steatosis can be associated with chronic HCV infection or with alcoholic liver disease. Also, Mallory’s hyalin is frequently found in alcoholic liver disease, but may also be detected in HCV patients [7]. However, both findings can be observed in metabolic disorders such as Wilson’s disease [3]. In PBC, lymphocytic infiltrations may resemble chronic HCV infection. Reactive bile duct proliferations, too, may be present in hepatic diseases other than PBC. Therefore, in the case reported here, it was impossible to clarify the etiology of liver cirrhosis without a doubt. Besides HCV infection, alcoholic liver disease and PBC could not be
ARTICLE IN PRESS 894
T. Kalinski et al. / Pathology – Research and Practice 202 (2006) 891–894
excluded. It is rather the total of findings which would have given a clue to the diagnosis. In this regard, renal failure was a significant finding. Although MPGN was diagnosed only after postmortem examination, a correlation between HCV infection and MPGN is known from the literature [2,4,6]. A prevalence of 60% for HCV infection in MPGN has previously been reported from Japan [10]. The pathogenesis of MPGN in HCV infection has been associated with a deposition of immune complexes containing hepatitis C antibodies, hepatitis C antigens, and complement, independent of the presence or absence of HCV-associated cryoglobulinemia [4]. However, acute renal failure is an expectable and severe complication in patients with advanced liver cirrhosis and ascites, known as hepatorenal syndrome. In contrast to MPGN, the morphology of renal biopsies in hepatorenal syndrome would be normal. One might speculate that a renal biopsy would have helped in finding the diagnosis in the case reported here. However, the prognosis was poor, since the liver cirrhosis had already been at an advanced stage. Nevertheless, if renal failure occurs concomitantly with liver cirrhosis, HCV infection should be considered, even if serological examinations fail to detect anti-HCV antibodies. In such cases, the molecular-genetic detection of HCV RNA by PCR is obviously inevitable. Besides HCV-RNA detection in blood samples, its detection in FFPE archival liver tissue has been shown to be a practicable method, even if specimens obtained by thin-needle biopsy are used [7]. In the present case, we applied this method to FFPE liver tissue obtained in a postmortem examination. Although there was an autolysis time of 1 day after death, HCV RNA was still detectable, and the cause of liver cirrhosis and concomitant MPGN was clearly identified. Therefore, we recommend this method for the detection of HCV infection in FFPE liver biopsies of similar cases in which blood analyses were not carried out or provided ambiguous or negative results. An early detection of HCV infection may lead to a favorable course of the disease if there is a response to therapy. Apart from hepatic and renal failure due to liver cirrhosis and MPGN, a staphylococcus aureus infection with abscesses in the myocardium was a severe complication in the case presented here. The circulatory shock, which was the cause of death, may be attributed to one of these disorders or to the combination of them.
We conclude that the diagnosis of HCV infection in cases of liver cirrhosis may require a molecular-genetic analysis. Concomitant MPGN should arouse suspicion of HCV infection. Specimens of FFPE liver tissue can be used for the detection of HCV RNA, even if the tissue was obtained in a postmortem examination.
References [1] S. Bellentani, G. Pozzato, G. Saccoccio, M. Crovatto, L.S. Croce, L. Mazzoran, F. Masutti, G. Cristianini, C. Tiribelli, Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study, Gut 44 (1999) 874–880. [2] D.M. Burstein, R.A. Rodby, Membranoproliferative glomerulonephritis associated with hepatitis C virus infection, J. Am. Soc. Nephrol. 4 (1993) 1288–1293. [3] R.S. Cotran, V. Kumar, S.L. Robbins, Cirrhosis of Wilson’s disease, in: R.S. Cotran, V. Kumar, S.L. Robbins (Eds.), Robbins Pathologic Basis of Disease, W.B. Saunders, Philadelphia, 1989, pp. 956–957. [4] L. Daghestani, C. Pomeroy, Renal manifestations of hepatitis C infection, Am. J. Med. 106 (1999) 347–354. [5] M. Danta, G.J. Dore, L. Hennessy, Y. Li, C.R. Vickers, H. Harley, M. Ngu, W. Reed, P.V. Desmond, W. Sievert, G.C. Farrell, J.M. Kaldor, R.G. Batey, Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection, Med. J. Aust. 177 (2002) 240–245. [6] R. Davda, J. Peterson, R. Weiner, B. Croker, J.Y. Lau, Membranous glomerulonephritis in association with hepatitis C virus infection, Am. J. Kidney Dis. 22 (1993) 452–455. [7] H.P. Fischer, E. Willsch, E. Bierhoff, U. Pfeifer, Histopathologic findings in chronic hepatitis C, J. Hepatol. 24 (1996) 35–42. [8] D.B. Strader, T. Wright, D.L. Thomas, L.B. Seeff; American Association for the Study of Liver Diseases, Diagnosis, management, and treatment of hepatitis C, Hepatology 39 (2004) 1147–1171. [9] S. Vogt, R. Schneider-Stock, S. Klauck, A. Roessner, C. Rocken, Detection of hepatitis C virus RNA in formalinfixed, paraffin-embedded thin-needle liver biopsy specimens, Am. J. Clin. Pathol. 120 (2003) 536–543. [10] H. Yamabe, R.J. Johnson, D.R. Gretch, K. Fukushi, H. Osawa, M. Miyata, H. Inuma, T. Sasaki, M. Kaizuka, N. Tamura, S. Tsunoda, Y. Fujita, K. Onodera, Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan, J. Am. Soc. Nephrol. 6 (1995) 220–223.