Liver fibrosis of hepatitis C virus infection in routine hemodialysis patients in Indonesia

Aida Lydia, Anindia Larasati, Rino Alvani Gani, Ikhwan Rinaldi

Background

The risk of hepatitis C virus (HCV) infection is increasing in patients under routine hemodialysis, but only some patients progress to liver fibrosis. This study was aimed to identify the prevalence of significant liver fibrosis in routine hemodialysis patients with hepatitis C infection as well as factors associated with liver fibrosis.

 

Methods

This cross-sectional study was conducted in three tertiary general hospitals (Cipto Mangunkusumo Hospital, Persahabatan Hospital, and Fatmawati Hospital) in Jakarta, Indonesia, among hemodialysis patients infected with HCV. Total sampling was used from May to September 2017 in hemodialysis unit of all hospitals. Sex, age, time at first diagnosis of HCV, duration of HCV infection, duration of hemodialysis, AST level, hepatitis B virus coinfection and diabetes mellitus were analyzed in association with significant liver fibrosis. Liver fibrosis was assessed using transient elastography and considered significant if the value was ≥7.1 kPa. Chi-square, Mann–Whitney U, and Fisher’s exact tests were used. Risk model was analyzed with logistic regression.

 

Results

Of the 133 hemodialysis patients infected with HCV, 71.4% of the subjects had significant liver fibrosis. In the risk model, male gender (odds ratio [OR] = 3.92; 95% confidence interval [CI] = 1.74–8.84; p < 0.001) and diabetes mellitus (DM) (OR = 2.85; 95% CI = 1.03–7.88; p = 0.043) were associated with significant liver fibrosis.

 

Conclusion

The prevalence of significant liver fibrosis in routine hemodialysis patients with hepatitis C infection was high. Male and DM were associated with significant liver fibrosis.

 

Keywords

hemodialysis, hepatitis C, liver fibrosis

Liver fibrosis is a chronic progressive liver damage characterized by the accumulation of extracellular matrix, which can lead to changes in liver architectures and ultimately develop into cirrhotic nodules.1,2 Patients with advanced liver fibrosis are at risk of having hepatocellular carcinoma with a rate of 1–2% per year.³ Fibrosis is considered significant when there is fibrosis with septa. This significant fibrosis is shown as fibrosis F2 by transient elastography.⁴

Hepatitis C is the most common cause of liver fibrosis, and its prevalence in hemodialysis patients varies from 4 to 60% worldwide.⁵⁻⁷ A meta-analysis conducted by Fabrizi et al,⁸ demonstrated positive hepatitis C virus (HCV) infection is a risk factor for mortality in hemodialysis patients with a relative risk of 1.35.⁹ Hemodialysis patients with HCV infection in Indonesia usually do not receive treatment, and data on the progression to liver cirrhosis have not been documented. HCV infection may also result in extrahepatic clinical manifestations, including cardiovascular, cerebrovascular, renal, and endocrine.¹⁰ The high HCV infection prevalence among hemodialysis patients and the fact that HCV infection contributes to a higher mortality rate in such patients mandate extra attention in this particular topic.

The greater degree of liver fibrosis is associated with progression to liver cirrhosis and death. Evaluation of liver fibrosis in HCV infection may have a role in the management and treatment plan. Transient elastography (TE) or FibroScan® is a noninvasive, easy, and rapid method to evaluate the degree of liver fibrosis. Kidney Disease Improving Global Outcomes (KDIGO) recommended liver fibrosis evaluation for patients with HCV infection to treatment initiation, liver fibrosis monitoring, and evaluation of possibility for kidney transplantation.¹¹ Some studies have been conducted to evaluate factors associated with liver fibrosis in patients with HCV infection who did not undergo hemodialysis. The factors include age >40 years at the time of infection, male gender, duration of HCV infection, concomitant infection with hepatitis B, diabetes mellitus (DM), and high transaminase level.¹²⁻¹⁵ However, only several studies have evaluated this issue in hemodialysis patients, and the result are varied.¹⁶ In Indonesia, no reports have yet documented regarding liver fibrosis in hemodialysis patients with HCV coinfection. Therefore, this study is aimed to evaluate the prevalence of significant liver fibrosis in hemodialysis patients with HCV infection and factors associated with the development of liver fibrosis.

 

 

This was a cross-sectional study in routine hemodialysis patients infected with HCV at the Hemodialysis Unit of Cipto Mangunkusumo Hospital, Persahabatan Hospital, and Fatmawati Hospital in Jakarta, Indonesia from May to September 2017. This study has been approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (No: 632/UN2.F1/ETIK/2017).

Jakarta, Indonesia from May to September 2017. This study has been approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (No: 632/UN2.F1/ETIK/2017). Subjects were recruited using total population sampling in all hemodialysis unit of three hospitals. There were 402 patients underwent routine hemodialysis in three hospitals (192 patients in Cipto Mangunkusumo Hospital, 90 patients in Persahabatan Hospital, 120 patients in Fatmawati Hospital) and the subjects were recruited based on anti-HCV positivity from medical record. The exclusion criteria were patients with any previous HCV treatment or HIV coinfection. All patients gave written consent, and subsequently, history taking and physical examination were performed. Transient elastography examination was carried out to identify significant (≥7.1 kPa, F2–F4) and nonsignificant (<7.1 kPa, F0–F1) liver fibrosis. All subjects were grouped based on sex, age at HCV infection (below or over the age of 40 years), duration of HCV infection (less or more than 10 years), duration of hemodialysis therapy, aspartate aminotransferase (AST) level, concomitant hepatitis B infection (with or without infection), and DM.

 

Statistical analysis

Statistical analyses were done using SPSS software version 20 (IBM Corp, USA). Chi-square test was used to analyze the association between significant liver fibrosis and DM, age at HCV infection, duration of hemodialysis therapy. Fisher’s exact test was used to analyze the association between sex, hepatitis B infection and significant liver fibrosis. Odds ratios (OR) were also calculated between variables. Mann– Whitney U test was used to analyze the association between AST level and significant liver fibrosis. A multivariate analysis using logistic regression was carried out to identify risk factors associated with significant liver fibrosis. All independent variables that have a p-value <0.25 in the bivariate analysis were entered into the logistic regression model. A p-value of <0.05 was considered statistical significance.

 

 

Of the 402 patients who had undergone hemodialysis, there were 156 patients infected with HCV in Cipto Mangunkusumo Hospital (n = 77), Persahabatan Hospital (n = 50), and Fatmawati Hospital (n = 27). However, 14 patients refused to participate in the study, 5 patients were not eligible for examination due to ascites and 4 patients died. No patient with HIV coinfection and previous history of HCV treatment was found. Thus, the study included 133 subjects. The mean (standard deviation [SD]) of age was 51.04 (12.9) years, and 75 (56.4%) subjects were men.

In the three hospitals, this study showed that as many as 95 of 133 subjects (71.4%; 95% CI = 63.74–79.06) had significant liver fibrosis. The characteristics of the subjects can be seen in Table 1.

 

 

Sex, age at infection, AST level were associated with significant liver fibrosis in bivariate analysis (Table 2). In multivariate analysis, only sex and DM became independent risk factors for significant liver fibrosis in patients with HCV infection who undergone hemodialysis (Table 2).

 

 

 

 

This study found 71.4% of routine hemodialysis patients infected with HCV had significant liver fibrosis. On the contrary, a study by Becker et al¹⁶ in Brazil showed only 23% of patients had significant fibrosis. A retrospective cohort study by Agarwal and Gupta¹⁷ in India, which was carried out between 1995 and 2015 showed that among 277 hepatitis C cases, 13.6% subjects had significant fibrosis. The differences may be resulted from younger age (34.05 [10.28] years old) and shorter duration of HCV infection (5.2 [4.0] months) in study from India.¹⁷

A previous study showed that male was an independent risk factor for the progression of liver fibrosis in patients with HCV infection who have normal renal function.¹⁸ That study also revealed male as risk factor for liver fibrosis (OR = 3.924; 95% CI = 1.741–8.842; p < 0.001) among hemodialysis patients coinfected with HCV.¹⁸ Our study also showed similar result. The higher risk of developing liver fibrosis in patient with HCV infection. Shimizu et al¹⁹ reported that estradiol at physiological doses suppressed the development of hepatic fibrosis both in vitro and in vivo models by inhibiting a collagen production, reducing an α-smooth muscle actin (α-SMA) expression, and reducing an intermediate filament expression called desmin. Both α-SMA and desmin are expressed by myofibroblast-like cells that originated from activated stellate cells. It also found that estradiol inhibits activated stellate cell spreading and DNA synthesis. The findings suggested that estradiol is a potent inhibitor of stellate cell transformation and thus plays some antifibrogenic role in the liver.¹⁹

The multivariate analysis showed that age at diagnosis of more than 40 years was not associated with higher risk of fibrosis progression. On the contrary, the study by Becker et al¹⁶ demonstrated that an estimated age at diagnosis of >40 years is an independent risk factor of liver fibrosis. Such differences may be related to different subject characteristics; Becker et al¹⁶ recruited younger subjects (36 [11] years old) than this study (51 [13] years), and it was difficult to accurately determine the age at hepatitis C diagnosis. Age at diagnosis generates the same effect on liver fibrosis in patients with chronic kidney disease and nonuremic individuals. A hypothesis has been proposed that the capacity of the immune system to overcome the pathological effects of hepatitis C is diminished with age.¹⁶ Moreover, it also has been demonstrated that age at the time of infection of over 40 years showed a higher proportion of significant liver fibrosis compared with those under 40 years of age.

There was also no evidence of higher risk of liver fibrosis progression between the duration of hepatitis C diagnosis and significant liver fibrosis in patients undergoing hemodialysis; the median in this study was 18 months. Dienstag et al¹⁴ with different population (patients with normal renal function). Santoro et al²⁰ showed that anti-HCV positive patients who had been diagnosed showed that the duration of having hepatitis C infection was associated to liver fibrosis with a mean duration of 17.5 years with liver fibrosis had a median of 10 years (4–16 years) since they started hemodialysis treatment.

No association between the duration of hemodialysis therapy and significant liver fibrosis may be because HCV has mild activity and it is not progressive in hemodialysis patients, which may be due to the immunological nature of those patients.²¹ This study showed that AST level did not have higher risk of liver fibrosis. AST was found to have an independent association with liver fibrosis in patients with uremia.¹⁶ In comparison with this study, the subjects included by Becker et al¹⁶ had a higher AST level, which may affect the results. AST may serve as a predictor of liver fibrosis in hemodialysis patients. Moreover, patients with a higher AST level must have strict monitoring since it may suggest more severe liver damage.¹⁶

Concomitant infection with hepatitis B was not shown to have higher risk of liver fibrosis in hepatitis C patient who had undergone hemodialysis (p = 0.439). The small number of subjects with hepatitis B in this study (n = 8) might be the reason for the nonsignificant result. Previous studies in patients with normal renal function conducted by Sagnelli et al²² and Caccamo et al,²³ concomitant infection of hepatitis B and hepatitis C has higher risk of more severe histological liver abnormalities.

It has been demonstrated that DM has higher risk of liver fibrosis in hemodialysis patient with HCV infection (p = 0.043). A study by Huang et al²⁴ in a general population has shown that DM is an independent risk factor for cirrhosis. DM in patients with hepatitis C infection accelerates the progression of fibrosis into cirrhosis and hepatocellular carcinoma, since from the pathogenesis point of view, it may cause liver steatosis. Diminished insulin sensitivity that occurs in DM may also increase the release of free fatty acid from the adipose tissues, and it may increase lipid hepatic deposition.¹⁵

Although this study was aimed to determine the prevalence of liver fibrosis in hemodialysis patients, it was revealed that the prevalence of hepatitis C is high in the three hospitals studied. The Indonesian Society of Nephrology issued a recommendation in 2006 to control the nosocomial transmission of HCV infection in hemodialysis units. Nowadays, the process of reusing dialyzer is carried out using separate machines. In the past, it was performed manually with formaldehyde without the use of automated equipment. Other factors considered to contribute to the decreasing prevalence of HCV infection is the increasing use of erythropoietin (EPO). The use of EPO decreases the need for a blood transfusion, which may eventually decrease the risk of transmission of HCV infection. A multicenter study at a hemodialysis unit showed that the incidence of hepatitis seroconversion had been reduced from 1.41% to 0% only per year by performing greater efforts on strict enforcement of universal precautions.²⁵ It indicates that good practice of universal precaution can prevent the nosocomial transmission of HCV infection in the hemodialysis unit and that the isolation of anti-HCV positive patients is not necessary.

However, this study has some limitations. First, this cross-sectional study may demonstrate weak evidence of a causal relationship between the variables studied. Second, it is difficult to know accurately when an HCV infection is diagnosed since it is asymptomatic; therefore, variables of the duration of HCV infection in this study was based on laboratory reports.

Based on this study, it can be concluded that the prevalence of significant liver fibrosis among hemodialysis patients with hepatitis C at the Hemodialysis Unit in Cipto Mangunkusumo Hospital, Persahabatan Hospital, and Fatmawati Hospital in was found in 71.4%. Male and DM were associated with significant liver fibrosis. Meanwhile, age at hepatitis C diagnosis, duration of hepatitis C infection, duration of hemodialysis, AST level, and concomitant hepatitis B infection did not show any association with significant liver fibrosis in this study.

 

 

 

 

 

 

 

1. Ramachandran P, Iredale JP. Reversibility of liver fibrosis. Ann Hepatol. 2009;8(4):283–91.
2. Rakela J, Vargas HE. Hepatitis C: magnitude of the problem. Liver Transpl. 2002;8(10 Suppl 1):S3–6.
3. Sherman KE. Advanced liver disease: what every hepatitis C virus treater should know. Top Antivir Med. 2011;19(3):121–5.
4. Tovo CV, Becker SC, Almeida PR, Galperim B, Chaves S. Progression of liver fibrosis in monoinfected patients by hepatitis C virus and coninfected by HCV and human immunodeficiency virus. Arq Gastroenterol. 2013;50(1):19–22.
5. Ramzi ZS, Abdulla AA, Al-Hadithi T, Al-Tawil N. Prevalence and risk factors for hepatitis C virus infection in hemodialysis patients in Sulaimani. Zanco J Med Sci. 2010;14(1):44–50.
6. Lee JW. Renal dysfunction in patients with chronic liver disease. Electrolyte Blood Press. 2009;7(2):42–50.
7. Agarwal SK, Dash SC, Gupta S, Pandey RM. Hepatitis C virus infection in haemodialysis: the ‘no-isolation’ policy should not be generalized. Nephron Clin Pract. 2009;111(2):c133–40.
8. Fabrizi F, Dixit V, Messa P. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat. 2012;19(9):601–7.
9. Ladino M, Pedraza F, Roth D. Hepatitis C virus infection in chronic kidney disease. J Am Soc Nephrol. 2016;27(8):2238–46.
10. Lee MH, Yang HI, Lu SN, Jen CL, You SL, Wang LY, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206(4):496–77.
11. Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2018 clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2018;8:91-165.
12. Oliveira AC, Bortotti AC, Nunes NN, El Bacha IA, Parise ER. Association between age at diagnosis and degree of liver injury in hepatitis C. Braz J Infect Dis. 2014;18(5):507–11.
13. Ceylan B, Yardimci C, Fincanci M, Tözalgan Ü, Eren G, Müderrisoğlu C, et al. Predictors of liver fibrosis in patients with chronic HCV Infection. Turkiye Klinikleri J Med Sci. 2012;32(6):1522–9.
14. Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology. 2011;54(2):396–405.
15. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol. 2009;15(13):1537–47.
16. Becker VR, Badiani RG, Lemos LB, Perez RM, Medina-Pestana JO, Lanzoni VP, et al. Factors associated with the progression of hepatic fibrosis in end-stage kidney disease patients with hepatitis C virus infection. Eur J Gastroenterol Hepatol. 2009;21(12):1395–9.
17. Agarwal SK, Gupta SD. Liver biopsy in patients on hemodialysis with hepatitis C virus infection. Indian J Nephrol. 2015;25(3):152–7.
18. Elvírez-Gutiérrez Á, Castellanos-Fernández MI, Santillán-López W, Dorta-Guridi Z, Galbán-García E, Arús-Soler E. Liver stiffness reference values for healthy Cuban adults. Medicc Rev. 2018;20(1):24–8.
19. Shimizu I, Mizobuchi Y, Yasuda M, Shiba M, Ma YR, Horie T, et al. Inhibitory effect of estradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut. 1999;44(1):127–36.
20. Santoro D, Mazzaglia G, Savica V, Li Vecchi M, Bellinghieri G. Hepatitis status and mortality in hemodialysis population. Ren Fail. 2009;31(1):6–12.
21. Zayed BEM, Elsharkawy A, Abdou M, Abd Al Fatah DS, El- Shabony TH. Assessment of hepatic fibrosis by fibroscan in Egyptian chronic hemodialysis patients with chronic hepatitis C (genotype 4): a single-center study. Saudi J Kidney Dis Transpl. 2017;28(4):764–73.
22. Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T, et al. Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis. Hepatology. 2000;32(5):1106–10.
23. Caccamo G, Saffioti F, and Raimondo G. Hepatitis B virus and hepatitis C virus dual infection. World J Gastroenterol. 2014;20(40):14559–67.
24. Huang YW, Yang SS, Fu SC, Wang TC, Hsu CK, Chen DS, et al. Increased risk of cirrhosis and Its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study. Hepatology. 2014;60(3):807–14.
25. Mohamed WZ. Prevention of hepatitis C virus in hemodialysis patients: five years experience from a single center. Saudi J Kidney Dis Transpl 2010;21(3):548–54.

Copyright @ 2019 Authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and source are properly cited.