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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 51  |  Issue : 2  |  Page : 182-185
Liver histology in patients on hemodialysis with chronic hepatitis C viral infection


Department of Pathology, M.S. Ramaiah Medical College, Bangalore, Karnataka, India

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   Abstract 

Hepatitis C virus (HCV) is a major cause of chronic liver disease in patients on hemodialysis. As no useful noninvasive predictors of disease activity and fibrosis have been found, liver biopsy is essential in these patients to accurately assess the severity of disease and thus the prognosis and plan management. The present study was undertaken to assess the degree of severity of necroinflammatory changes and fibrosis in liver biopsies of patients on hemodialysis with chronic HCV infection. Liver biopsies obtained from 45 patients on hemodialysis with serological evidence of chronic hepatitis C were studied. The grading of necroinflammatory activity and staging of fibrosis were histologically assessed. The majority of patients (30, i.e. 66.7%) had mild disease with mild inflammatory activity and stage 0, 1 or 2 fibrosis. There was no significant correlation between the degree of fibrosis and the age of the patients (rs = 0.015), the duration of hemodialysis (rs = 0.047) or the presence of steatosis (rs = 0.064). There was a positive correlation between the presence of bile ductular proliferation and the severity of fibrosis (rs = 0.612). It was concluded that chronic HCV infection in hemodialysis patients is relatively mild early in its course. However, serial follow-up liver biopsies are mandatory to plan appropriate intervention strategies.

Keywords: Hemodialysis, chronic hepatitis, hepatitis C, liver biopsy, histology, staging

How to cite this article:
Mysorekar VV, Rao SG, Mahadeva K C. Liver histology in patients on hemodialysis with chronic hepatitis C viral infection. Indian J Pathol Microbiol 2008;51:182-5

How to cite this URL:
Mysorekar VV, Rao SG, Mahadeva K C. Liver histology in patients on hemodialysis with chronic hepatitis C viral infection. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 Oct 14];51:182-5. Available from: http://www.ijpmonline.org/text.asp?2008/51/2/182/41648



   Introduction Top


Hepatitis C virus (HCV) is a major cause of chronic liver disease in patients on hemodialysis. The introduction of anti-viral agents and the potential for patients with chronic HCV infection to develop liver failure, where transplantation should be considered, or hepatocellular carcinoma where early recognition is critical, demands more accurate assessment of the stage of disease. The liver in chronic HCV infection may develop fibrosis or cirrhosis in the absence of symptoms, clinical signs, abnormal serum liver function tests or viraemia. [1] Currently, no useful noninvasive predictors of disease activity and fibrosis have been found in hemodialysis patients. [2] Hence, liver biopsy is essential in these patients to accurately assess liver pathology, establish the grade and stage of liver disease, predict the disease outcome and plan management.

The present study was undertaken to assess the degree of severity of necroinflammatory changes and fibrosis in liver biopsies of patients on hemodialysis with chronic HCV infection.


   Materials And Methods Top


The present study was conducted at the Department of Pathology, M.S. Ramaiah Medical College, Bangalore. Liver biopsies were performed on 45 patients (32 males and 13 females) of end-stage renal disease on hemodialysis who showed evidence of chronic liver disease. These patients had presented with jaundice, serum bilirubin levels ranging between 1.2 and 3.7 mg/dl and showed abnormal liver enzymes, especially increased serum alanine aminotransferase (ALT) level. Their serum tested positive for anti-HCV and HCV RNA. All the patients showed serological negativity for hepatitis B viral markers, HBsAg and HBV DNA. Patients with evidence of autoimmune hepatitis, earlier anti-viral or immunosuppressive therapy, history of use of known hepatotoxic drugs or chronic alcohol intake (>80 g/day for 5 years) were excluded from the study.

The liver biopsy tissue was fixed in 10% buffered formalin and processed in the conventional manner. Haematoxylin and Eosin (H and E) and Masson's trichrome-stained sections were studied in each case. The degree of histological necroinflammatory activity (grade) and fibrosis (stage of liver disease) was assessed as described by Ishak et al . [3] The scoring was done by at least two pathologists, independently. The necroinflammatory scores were determined by taking into account the following features:

  1. Periportal or periseptal interface hepatitis (piecemeal necrosis): Scores 0-4.
  2. Confluent necrosis: Scores 0-6.
  3. Focal (spotty) lytic necrosis, apoptosis and focal inflammation: Scores 0-4.
  4. Portal inflammation: Scores 0-4.


Thus, the maximum possible score for grading was 18. In addition, other commonly seen features in chronic HCV infection were noted but not scored. The features were:

  1. Ballooning degeneration
  2. Fatty change (steatosis)
  3. Lymphoid aggregates
  4. Bile duct inflammation and damage
  5. Bile ductular proliferation
  6. Cholestasis
  7. Hepatocellular dysplasia


Fibrosis was assigned a score of 0-6, where the maximum score of 6 indicated definite cirrhosis.


   Results Top


The age of the patients ranged from 10 to 84 years (mean = 46.2 years). The duration of hemodialysis in these patients ranged from 1 to 4 years (mean 2.1 years).

[Table - 1] shows the grading of activity and staging of fibrosis in various cases. The number of cases in various subcategories of histological changes is depicted as a bar diagram [Figure 4]. The majority of patients had mild disease with mild inflammatory activity and stage 0, 1 or 2 fibrosis. The inflammatory cells seen in all the cases were predominantly mononuclear cells constituted by lymphocytes and plasma cells with a few macrophages. Only about half the cases showed confluent necrosis, which was restricted to focal areas; only two cases showed prominent bridging necrosis. A single case showed definite cirrhosis (stage 6 fibrosis). In three biopsies, dysplastic hepatocytes were evident.

There was no significant correlation between the degree of fibrosis and the age of the patients ( r s = 0.015) or the duration of hemodialysis ( r s = 0.047). There was a positive correlation between the presence of bile ductular proliferation and the severity of fibrosis ( r s = 0.612). Thus, all the six cases with bile ductular proliferation showed fibrosis of stage 3 or higher. Only 10 of the 45 biopsies showed steatosis. However, there was no significant correlation between the presence of steatosis and the degree of fibrosis ( r s = 0.064).


   Discussion Top


The incidence of HCV positivity in chronic liver disease reported from the Indian subcontinent ranges between 4 and 53%. [4] Over 80% of patients with acute hepatitis C go on to develop chronicity, but only 20-25% are known to develop end-stage liver disease and its complications. [5] Some authors have shown that an older age (above 40 years) at infection [6],[7],[8],[9] and alcohol abuse [6],[7],[8] are associated with more advanced fibrosis in chronic hepatitis C. In the present study as well as in the study by Boyacioglu et al , [2] no correlation has been found between the degree of fibrosis and the age of the patient. The duration of infection was uncertain, as all the patients in the present study had undergone multiple sessions of hemodialysis and the exact date of infection could not be traced. However, it was found that the duration of hemodialysis had no influence on the severity of the liver disease as has also been noted by Boyacioglu et al . [2] Other studies have found no relationship between the degree of histological activity or the degree of fibrosis and the serum transaminase levels. [2],[10],[11],[12] Even the HCV-RNA titre [2],[8] or HCV genotype [8] does not appear to determine the progress of the disease. This emphasizes the importance of grading and staging of liver biopsy lesions in determining the progress of chronic hepatitis C. In dialysis patients, the severity of existing liver disease on a pre-transplantation liver biopsy may provide useful prognostic information about the outcome of liver disease after renal transplantation. [11],[13]

In the present study, it was found that, in general, dialysis patients with hepatitis C infection had mild necroinflammatory changes with a low proportion of bridging fibrosis or cirrhosis. Similar findings have been described by other authors. [12],[14],[15] Toz et al , [15] recorded an average grade of 4.30 2.98 and stage of 1.08 1.02 in liver biopsies of dialysis patients with hepatitis C. These scores are lower than those obtained in the present study. Hemodialysis increases markedly the serum levels of hepatocyte growth factor (HGF) so that the regular dialysis treatment mimics the regular administration of HGF as a drug. [16] This is one reason for the more benign nature of HCV-related liver disease in patients on hemodialysis. Uraemia-associated impaired immunoreactivity may be another explanation for the more favourable course of hepatitis C virus infection in uraemic patients. [17]

Steatosis has been found to exacerbate fibrosis in chronic hepatitis C. [18] Clouston et al , [18] hypothesize that impaired hepatocyte replication in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells, which are capable of differentiating into both biliary and hepatocyte lineages. They suggest that the resultant ductular reaction triggers fibrosis at the portal tract interface. In the present study, there was a positive correlation between the presence of bile ductular proliferation and the severity of fibrosis. However, no such correlation was evident between the presence of steatosis and the degree of fibrosis, probably because the steatosis was not very severe in the 10 cases where it was seen.

Patients with high-grade necroinflammation, septal fibrosis and regions of nodularity on initial biopsy are at a high risk of developing advanced cirrhosis in the ensuing decade. [19] Severe fibrosis is also a risk factor for the development of hepatocellular carcinoma. [20] The prevalence of dual HBV and HCV infection is 3%. [21] Sakhuja et al , [22] have found that dual HBV and HCV infection is associated with more severe liver disease. A higher risk of hepatocellular carcinoma has also been noted in such patients. [4],[21] In the present study, there was no case of dual HBV and HCV infection. Dysplastic hepatocytes are probably precursors of hepatocellular carcinoma [23] and hence a regular follow-up is necessary in our three cases where they were seen.

Treatment with interferon is recommended if there is significant fibrosis (HAI score ≥3, METAVIR score ≥F2) or inflammation. [24] The treatment is costly and may have side effects. Some patients tolerate therapy very poorly and become severely anaemic, often needing expensive interventions. Patients with a fibrosis stage 1 or 2 might not have to undergo treatment and can avoid such potential complications.

Krahn et al , [25] have estimated that only 14% of transfused patients with chronic hepatitis C virus infection develop cirrhosis within 20 years, but 1 in 4 will eventually develop cirrhosis and 1 in 8 will die of liver disease. Wong et al , [1] recommend a follow-up biopsy at 5 years for stage 0-2 fibrosis and at 3 years for stage 3 or greater fibrosis. In the present study, majority of the patients had only stage 0, 1 or 2 fibrosis. However, it is possible that in the present situation, prospective studies over a period of a decade or more will identify a significant proportion of those who were thought to have benign disease progressing to more significant fibrosis. In the event of a patient on hemodialysis receiving a renal transplant, the immunosuppression is expected to cause a rapid progression of the liver disease by aggravating septal fibrosis and confluent necrosis. [26],[27],[28] Seth et al , [26] observed an increase in necroinflammatory score of 2 or more in 60% renal allograft recipients over a period of 25.5 months, with 18.7% dying of liver failure at median 27 months (range 11-53 months) since renal transplantation. Serial liver biopsies will have to be performed for a proper follow-up under these circumstances.


   Conclusion Top


Chronic hepatitis C viral infection in hemodialysis patients is relatively mild early in its course. Liver biopsy is indicated to accurately assess the severity of the disease and select patients who require interferon therapy. Serial follow-up liver biopsies are mandatory to plan appropriate intervention strategies.[Figure 1],[Figure 2],[Figure 3].

 
   References Top

1.Wong VS, Baglin T, Beacham E, Wight DD, Petrik J, Alexander GJ. The role for liver biopsy in haemophiliacs infected with the hepatitis C virus. Br J Haematol 1997;97:343-7.  Back to cited text no. 1    
2.Boyacioglu S, Gur G, Yilmaz U, Korkmaz M, Demirhan B, Bilezikηi B, et al . Investigation of possible clinical and laboratory predictors of liver fibrosis in hemodialysis patients infected with hepatitis C virus. Transplant Proc 2004;36:50-2.  Back to cited text no. 2    
3.Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al . Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9.  Back to cited text no. 3    
4.Vaiphei K, Pal NS, Arora SK. Comparative analysis of HBV and HCV infection in hepatocellular carcinoma and chronic liver disease: An autopsy based study. Indian J Pathol Microbiol 2006;49:357-61.  Back to cited text no. 4    
5.Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D, Easley K. The role of liver biopsy in chronic hepatitis C. Hepatology 2001;33:196-200.  Back to cited text no. 5    
6.Wawrzynowicz-Syczewska M, Kubicka J, Lewandowski Z, Boron-Kaczmarska A, Radkowski M. Natural history of acute symptomatic hepatitis type C. Infection 2004;32:138-43.  Back to cited text no. 6    
7.Danta M, Dore GJ, Hennessy L, Li Y, Vickers CR, Harley H, et al . Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection. Med J Aust 2002;177:240-5.  Back to cited text no. 7    
8.Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR and DOSVIRC groups. Lancet 1997;349:825-32.  Back to cited text no. 8    
9.Costa LB, Ferraz ML, Perez RM, Ferreira AS, Matos CA, Lanzoni VP, et al . Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection. Braz J Infect Dis 2002;6:219-24.  Back to cited text no. 9    
10.Rozario R, Ramakrishna B. Histopathological study of chronic hepatitis B and C: a0 comparison of two scoring systems. J Hepatol 2003;38:223-9.  Back to cited text no. 10    
11.Martin P, Carter D, Fabrizi F, Dixit V, Conrad AJ, Artinian L, et al . Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000;69:1479-84.  Back to cited text no. 11    
12.Cotler SJ, Diaz G, Gundlapalli S, Jakate S, Chawla A, Mital D, et al . Characteristics of hepatitis C in renal transplant candidates. J Clin Gastroenterol 2002;35:191-5.  Back to cited text no. 12    
13.Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with end-stage renal disease. Hepatology 2002;36:3-10.  Back to cited text no. 13    
14.Zacks SL, Fried MW. Hepatitis B and C and renal failure. Infect Dis Clin North Am 2001;15:877-99.  Back to cited text no. 14    
15.T φz H, Ok E, Yilmaz F, Akarca US, Erensoy S, Zeytinoπlu A, et al . Clinicopathological features of hepatitis C virus infection in dialysis and renal transplantation. J Nephrol 2002;15:308-12.  Back to cited text no. 15    
16.Rampino T, Arbustini E, Gregorini M, Guallini P, Libetta C, Maggio M, et al . Hemodialysis prevents liver disease caused by hepatitis C virus: Role of hepatocyte growth factor. Kidney Int 1999;56:2286-91.  Back to cited text no. 16    
17.Luzar B, Ferlan-Marolt V, Brinovec V, Lesnicar G, Klopcic U, Poljak M. Does end-stage kidney failure influence hepatitis C progression in hemodialysis patients? Hepatogastroenterology 2003;50:157-60.  Back to cited text no. 17    
18.Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis. Hepatology 2005;41:809-18.  Back to cited text no. 18    
19.Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, et al . The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334-40.  Back to cited text no. 19    
20.Tokita H, Fukui H, Tanaka A, Kamitsukasa H, Yagura M, Harada H, et al . Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy. J Gastroenterol Hepatol 2005;20:752-8.  Back to cited text no. 20    
21.Xess A, Kumar M, Minz S, Sharma HP, Shahi SK. Prevalence of hepatitis B and hepatitis C virus coinfection in chronic liver disease. Indian J Pathol Microbiol 2001;44:253-5.  Back to cited text no. 21    
22.Sakhuja P, Malhotra V, Gondal R, Sarin SK, Thakur V. Histological profile of liver disease in patients with dual hepatitis B and C virus infection. Indian J Pathol Microbiol 2003;46:555-8.  Back to cited text no. 22    
23.Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513-20.  Back to cited text no. 23    
24.Siegel CA, Suriawinata AA, Silas AM, Van Leeuwen DJ. Liver biopsy 2005: When and how? Cleve Clin J Med 2005;72:199-224.  Back to cited text no. 24    
25.Krahn M, Wong JB, Heathcote J, Scully L, Seeff L. Estimating the prognosis of hepatitis C patients infected by transfusion in Canada between 1986 and 1990. Med Decis Making 2004;24:20-9.  Back to cited text no. 25    
26.Seth AK, Anand AC, Singhal A. Hepatitis C in renal allograft recipients: Profile and genotypes in India. Indian J Gastroenterol 2005;24:A9.  Back to cited text no. 26    
27.Perez RM, Ferreira AS, Medina-Pestana JO. Is hepatitis C more aggressive in renal transplant patients than in patients with end-stage renal disease? J Clin Gastroenterol 2006;40:444-8.  Back to cited text no. 27    
28.Fabrizi F, Martin P, Ponticelli C. Hepatitis C virus infection and renal transplantation. Am J Kidney Dis 2001;38:919-34.  Back to cited text no. 28    

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Correspondence Address:
Vijaya V Mysorekar
89, A.G.s Office Colony, 5th Main, 6th Cross, RMV Extension Stage II, New BEL Road, Bangalore - 560 054,Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.41648

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    Figures

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