Abstract
There are conflicting results in studies concerning the best marker for liver histopathological features of HCV infection in HD patients. We planned a prospective study to follow HCV viremia and laboratory parameters of HD patients and correlate these with clinic features and histopathological findings. We included 68 HCV infected patients (45 male, 23 female, age: 39.8 ± 11.9 years, HD duration: 58.2 ± 36.4 months) in our study. The follow-up period after the biopsy was 33.2 ± 20.3 months. Patients liver enzyme (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT)) levels were determined monthly and ferritin levels every three months, and the mean value was recorded. We also screened patients for HCV RNA. During the follow-up period, 22 (32.4%) of the patients had positive RNA, 26 (38.2%) negative RNA, 20 (29.4%) had intermittent RNA positivity. The patients with high grade of portal necroinflammatory activity had significantly higher AST and ALT levels. In addition patients with high grade lobular activity had significantly shorter HD and HCV infection duration and higher AST, ALT and ferritin levels. AST levels were negatively correlated with duration of HD and HCV infection, and positively correlated with GGT and ferritin levels. Additionally, we found that ALT levels were negatively correlated with HD duration and positively correlated with GGT levels. ALT levels higher than 30 U/L were reflected necroinflammatory activity more significantly than levels higher than 40 U/L. Cirrhosis was detected in 5.9% of the patients, and we could not find any laboratory parameter that was correlated with stage of fibrosis. Although there is a high degree of liver involvement, cirrhosis is a relatively less frequent finding in HD patients. Serum aminotransferases and ferritin levels but not the pattern of HCV viremia are predictors of necroinflammatory activity in liver biopsy specimens. Liver biopsy obligatory to assess the disease activity in HD patients.
INTRODUCTION
Hepatitis C virus (HCV) infection is highly prevalent among patients with end stage renal disease (ESRD) and has an important role in the development of liver disease Citation[[1]]. Although the course of HCV infection is usually subclinical in HD patients, a substantial proportion of patients have chronic hepatitis and/or cirrhosis in histological evaluation Citation[[2]].
The presence of anti-HCV was associated with a poor prognosis in ESRD patients either during dialysis therapy or after renal transplantation. The severity of pre-transplant liver disease has been reported to be an important predictor of adverse post-transplant outcome Citation[3-5]. Following the studies reporting a high percentage of liver damage in HD patients, it is wise to perform liver biopsy to the potential renal transplant candidates.
Searches for a noninvasive parameter for the determination of the severity of liver disease have not yet found a sensitive marker. The presence of chronic hepatitis has been found to be poorly reflected by transaminase levels in dialysis patients Citation[6-7]. Similarly, presence of HCV viremia was not always associated with abnormal liver pathology in different studies Citation[6-8]. Another marker, ferritin has been studied in nondialysis patients and a positive correlation has been found between iron deposition, severity of HCV hepatitis, and impaired response to interferon therapy Citation[[9]]. A positive linear relationship between ferritin and aminotransferase levels in HD patients has been reported Citation[[10]]. Ferritin levels could be influenced by many factors and the sensitivity of high ferritin levels reflecting the degree of liver damage in HD population needs to be further studied.
We planned this study to evaluate the liver biopsy findings in HD patients and to find out if there was any correlation of liver histopathological findings with clinical features and laboratory parameters (HCV viremia, aminotransferases, gamma glutamyl transferase (GGT) and ferritin levels) during the follow-up period.
MATERIAL AND METHODS
We included 68 HCV infected patients (45 male, 23 female, age: 39.8 ± 11.9 years, HD duration: 58.2 ± 36.4 months) in our study. Patients who had received interferon were excluded from the study. None of the patients had history of alcohol abuse. Renal failure etiology of the patients was classified as tubuloinstertitial nephritis in 28 (41.2%), glomerulonephritis in 16 (23.5%), atherosclerosis in 9 (13.2%), amyloidosis in 7 (10.3%) and others in 8 (11.8) of the patients.
Estimated duration of HCV infection was determined from hospital records and information about the time interval from first risk factor exposure and was calculated as 44.2 ± 18.0 months. Liver biopsy was performed to all of the patients and the mean follow-up period after the biopsy was 33.2 ± 20.3 months. The patients laboratory parameters and pattern of HCV viremia was recorded prospectively after the liver biopsy. The patients were dialyzed in separate rooms and machines, according to their HCV viremia status. The dialysis prescription in our study included 4–5 h of HD using standard cuprophane membranes and an average blood flow rate of 300 mL/min. The maintained mean Kt/V of the patients was 1.42 ± 0.6.
Patients' liver enzyme (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and GGT) levels were determined monthly with standard automated analyzers. The normal range for our laboratory is 11–41 U/L for AST, 10–40 U/L for ALT and 11–61 U/L for GGT. Ferritin levels were measured every three months by chemiluminescence method (The Immulite Automated Immunoassay kit, Diagnostic Products Corporation, Los Angeles, USA), and the mean value was recorded. Anti-HCV was investigated using a third-generation ELISA test (Axsyon; Abbot, USA) that detects antibodies to four different regions of the hepatitis C virus, namely, HCr43 (core structural protein and nonstructural protein NS3), c22 (encodes the NS3 and NS4), C100-3 (nonstructural protein NS3 and NS4), and NS5 (putative HCV nonstructural protein NS5). We also screened patients for HCV RNA every three months and divided the patients into three groups as, patients with viremia, without viremia and intermittent viremia. HCV-RNA was detected using RT-PCR. All tests were performed and interpretended strictly in accordance with the manufacturers' instructions.
All liver biopsies were obtained by using the 18-gauge biopsy needle. Specimens were fixed in formalin and embedded in paraffin. Sections were cut at 3 µm and stained with hematoxylin and eosin, Masson's trichrom, Gomori reticulin stain, Perls' Prussian blue. All of the specimens were blindly reviewed by the study pathologist. The histological grade (necroinflammatory activity) and histological stage (degree of fibrosis) were determined using a combination of several proposed schemes Citation[11-13]. Presence of iron deposits was estimated according to the system of LeSage et al. Citation[[14]].
Patients were divided into two groups according to the severity of each histopathological feature as having low and high grade of necroinflammatory activity (grade 0,1,2 and 3,4); low and high stage of fibrosis (stage 0,1,2 and 3,4); and finally low and high degree of iron deposition (degree 0,1,2 and 3,4). We planned to compare the patient groups clinical features (HD and HCV duration, gender, HCV viremia) and laboratory parameters (AST, ALT, GGT, and ferritin levels). We also set up three different ranges for the upper limit for aminotransferases (AST > 41 U/L and ALT > 40 U/L; AST and ALT > 30 U/L; AST and ALT > 20 U/L) and looked for how they reflected the liver histopathological findings. We planned to search for the correlation of liver biopsy findings with each other. Additionally we aimed to investigate if any association existed between duration of HD and HCV infection and laboratory parameters including aminotransferases, GGT and ferritin levels.
Statistical Analysis
All values were expressed as mean ± SD, and were analyzed using the software SPSS 7.5 for Windows Windows (SPSS Inc., Chicago, IL, and U.S.A.). Differences between group parameters were measured using the Student's t-test. Chi-square analysis was used for categorical values. Bivariate analysis was used for correlation of independent parameters. The criterion for statistical significance was p < 0.05.
RESULTS
There was no evidence of clinical liver disease in our patient group. The mean AST and ALT levels of the patients during the follow-up period were 41.6 ± 29.1 U/L and 42.1 ± 32.0 U/L respectively. When we followed the presence of HCV viremia in the study group, 22 (32.4%) of the patients had positive RNA, 26 (38.2%) negative RNA, 20 (29.4%) had intermittent RNA positivity.
The results of the histopathological findings were shown in . We grouped the patients according to the histopathological findings and we compared the patient groups in terms of clinical features and laboratory parameters. The results were shown in . When we compared the mean GGT levels of the patients with histopathological features we found that GGT levels were significantly lower in patients with low degree of iron deposition (GGT 51.4 ± 79.6 U/L and 88.0 ± 59.8 U/L, respectively, p < 0.02). We also looked for the impact of gender and HCV viremia on liver histopathological findings and we did not find any significant difference between the liver biopsy findings of the patient groups.
Table 1. Liver Histopathological Changes Among HCV Infected Hemodialysis Patients
Table 2. Comparison Results of Laboratory Parameters of the HCV Infected Patients When They Were Grouped According to HCV Viremia and Liver Biopsy Findings
HCV Viremia and Results of the Correlation with Laboratory Parameters
When we compared the laboratory parameters of ALT, AST, GGT, and ferritin levels of the patients according to the HCV viremia status we did not find any statistical difference between these parameters in these patient groups (AST: 40.5 ± 24.9 U/L, ALT: 37.5 ± 23.5 U/L, GGT: 42.1 ± 34.8 U/L, ferritin: 708.4 ± 567.9 ng/mL in patients with viremia, AST: 40.8 ± 31.4 U/L, ALT: 37.4 ± 32.3 U/L, GGT: 54.2 ± 93.9 U/L, ferritin: 468.64 ± 462.7 ng/mL in patients without viremia, and AST: 43.7 ± 29.9 U/L, ALT: 53.2 ± 36.5 U/L, GGT: 64.2 ± 49.2 U/L, ferritin: 529.3 ± 428.9 ng/mL in patients with intermittent viremia).
Results of the Analysis When We Searched Whether High Amitransferase Levels Reflected Liver Histopathological Findings
At the first step we investigated how high AST, ALT levels (the upper limit set up by the laboratory for normal population, AST > 41 U/L and ALT > 40 U/L) reflected the liver histopathological findings. The AST levels were higher than 41 U/L in 28.8% and 37.5% of the patients with low- and high-grade portal necroinflammatory activity whereas these ratio was 25% and 68.7%, respectively for ALT levels (p < 0.001). When we searched for the percentage of high aminotransferases in the patients with low or high grade of lobular activity, we found that high ALT levels were significantly less frequent in patients with low grade lobular inflammatory activity (AST 23.6% and 40%, p > 0.05 and ALT 23.6% and 50%, p < 0.02). When we set up the upper range of AST and ALT to 30 U/L, we found that high ALT levels reflected more significantly the presence of high grade of portal and lobular necroinflammatory activity (ALT: 30.7% and 81.2% for low and high grade portal inflammatory activity, p < 0.0001 and 28.9% and 45% for low and high grade lobular inflammatory activity, p < 0.001). On the other hand percentage of patients with high AST levels was not significantly different in groups with low and high degree of necroinflammatory activity when the upper range was set up at 30 U/L (AST: 94.2% and 100% for low and high grade portal inflammatory activity, p > 0.05 and 94.7% and 96.6% for low and high grade lobular inflammatory activity, p > 0.05). We did not find any result that could predict the grade of liver necroinflammatory activity more significantly for both of the aminotransferases at upper range of 20 U/L. When we performed a similar correlation for aminotransferases and stage of fibrosis, we did not find any significant result. The correlation revealed a significantly lower percentage of patients whose ALT > 30 U/L in the group with low degree of iron deposition than those with high degree of iron deposition (ALT: 29.2% and 55.5% for low and high degree of iron deposition, p < 0.03).
Correlation Results of Liver Histopathological Findings with Each Other
Patients with a high grade of portal inflammatory activity had significantly higher percentage of high-grade of lobular inflammatory activity (68.7% and 36.5%, respectively, p < 0.02), high degree of fibrosis (62.5% and 19.6%, respectively, p < 0.001), more severe iron deposition (68.7% and 30.7%, respectively, p < 0.007) than patients with low grade of portal inflammatory activity. Additionally high stage of fibrosis was more frequent in patients with a high grade of lobular activity than those with a low grade of lobular activity (50%, and 15.7%, respectively, p < 0.001). There was no significant correlation of lobular necroinflammatory activity and fibrosis with the degree of iron deposition.
Bivariate Analysis Results of Duration of HD and HCV Infection with Laboratory Parameters
According to the bivariate analysis, AST levels were negatively correlated with duration of HD (p: 0.003, r: −, 357) and HCV infection (p: 0.02, r: −, 273), and positively correlated with GGT (p: 0.0001, r:, 465) and ferritin (p: 0.004, r:, 349) levels. Additionally, we found that ALT levels were negatively correlated with HD duration (p: 0.04, r: −, 238) and positively correlated with GGT levels (p: 0.0001, r:, 535). Patients' ALT levels were not found to be correlated with HCV duration and ferritin levels.
DISCUSSION
Hepatitis C virus is the most common cause of acute and chronic hepatitis in dialysis patients, and anti-HCV antibody positivity has been reported in 5% to 82% of patients on maintenance HD Citation[15-17]. The chronic course of HCV infection ranges from a carrier state with minimal hepatic pathology to rapidly progressive chronic active hepatitis and cirrhosis. Liver biopsy has been accepted as the golden test predicting the disease progression and response to therapy in HCV infected non-dialysis population. A low baseline HCV RNA level and mild liver pathology were found to be favorable prognostic factors for sustained virological and biochemical responses to interferon in HD patients Citation[[18]]. Presence of HCV infection and biopsy proven cirrhosis were found to be independent prognostic factors of 10-year survival in renal transplant recipients Citation[[5]]. These studies signify the importance of liver biopsy in the determination of liver damage in HD patients.
There is still argument about the sensitivity serum aminotransferases in reflecting liver damage in HD patients. In most of the studies, there is a lack of correlation between liver biopsy findings and serum aminotransferase levels in HD patients Citation[7-8], Citation[[19]]. In most of the patients with histological active hepatitis aminotransferases were in normal ranges. This finding was explained by the fact that the normal ranges for aminotransferases were lower in dialysis patients Citation[20-21]. In our study we performed a detailed evaluation of liver biopsy to find out if they could be reflected by any clinical parameter. According to our experience, the HD patients with high-grade portal and lobular inflammatory activity had significantly higher aminotransferase levels. When we searched how AST and ALT levels higher than 40 U/L reflected liver histopathological findings we found that ALT levels were higher than this value in 68.7% and 50% of patients with high-grade portal and lobular necroinflammatory activity. These differences became more significant for ALT levels when we set the upper range aminotransferases to 30 U/L. It should be noted that the mean aminotransferase levels of our patient group were higher than those reported in most of the studies Citation[[10]], Citation[20-21] and similar to the report of Roth et al. Citation[[22]]. We suggest that higher aminotransferases might be the result of acquired factors such as higher degree of iron deposition in our patient population. The underlying factor should be further studied.
Various studies have noted a wide range in the prevalence of HCV viremia in HD patients Citation[23-24]. Serial measurements of HCV load by bDNA assay showed three distinct patterns of viremia as persistent and intermittent viremia and HCV-RNA-negative individuals Citation[[24]]. The predictory of HCV viremia on biochemical tests and histological pattern has been argued Citation[6-7], Citation[[24]]. In our study there was a high prevalence of HCV viremia as 70.6% in our patients with HCV infection. We did not find any correlation between any of the laboratory parameters or histopathological findings with pattern of HCV viremia. These results suggest that HCV viremia cannot be accepted as a guide to decide the severity of histopathological damage in HD patients.
Liver histology has been found to be abnormal in most of the HCV infected HD patients. Chronic active hepatitis has been reported in 17.6–100% of the HD patients in various studies Citation[6-7], Citation[[25]]. Fortunately, except for Martin et al. who have found cirrhosis in 11% of the patients Citation[[19]], cirrhosis has been diagnosed in less than 10% of the ESRD patients in the rest of the studies Citation[6-7], Citation[[25]]. We also observed a wide spectrum of liver involvement in our HD population. There were various degrees of portal and lobular inflammatory activity in 97.1% and 95.6% and fibrosis in 88.2% of the patients. As liver biopsy findings have predictory role in liver disease progression in HD and pre-transplant patients, we suggest that liver biopsy should be a routine diagnostic test before renal transplantation. Our study result revealed a substantial percentage of patients with mild to moderate iron deposition and severe deposition in 25% of the patients, a value higher than the literature Citation[[7]], Citation[[26]]. When we looked for the link between iron deposition and histopathological findings, we found a significant association between portal inflammatory activity and degree of iron deposition. These results were in contrast to the study of Caramelo et al. who did not find any correlation of liver biopsy findings with degree of iron deposition in dialysis patients Citation[[7]]. The laboratory reflection of iron deposition was significantly higher in ferritin levels in patients with severe portal and lobular inflammatory activity. Additionally we found that serum ferritin levels reflected the severity of liver iron deposition and was significantly correlated with AST levels. A significant association between the levels of plasma aminotransfases and ferritin in HCV infected HD patients has been reported Citation[[10]]. This positive linear relationship could be explained on the basis of the aggregating effect of iron overload on HCV-induced liver damage. Our study results suggest that ferritin levels can be used in combination with aminotransferase levels for the prediction of necroinflammatory activity in HD patients. Unfortunately, the stage of fibrosis was not reflected by any of the laboratory parameters, including aminotransferases, GGT and ferritin levels. This finding can be explained by a lower prevalence of liver cirrhosis in our study group that will make it difficult to find any clinical correlates. Despite the wide spectrum of liver involvement, liver failure and cirrhosis are rare causes of death in HD patients. In our study although there is great percentage of liver involvement there was only 5.9% of cirrhosis in our patient group, a ratio similar to the literature and much lower than non-dialysis population. The slower progression of liver damage in dialysis patients and relatively lower incidence of cirrhosis is a subject of interest. One explanation is that the time for the development of liver failure exceeds the mean life expectancy of most HD patients. Rampino et al. explained the more benign course of HCV infection by the influence of marked and prolonged release of hepatocyte growth factor in HD patients Citation[[27]]. Interestingly, we found that duration of HD was significantly shorter in patients with more severe lobular necroinflammatory activity. Similarly iron deposition was significantly higher in patients with a shorter duration of HCV infection. According to bivariate analysis, aminotransferase levels were negatively correlated with HD and HCV duration. As presence of a higher grade of lobular inflammatory activity predicts the progression to an advanced stage of fibrosis, this finding can be accepted as the protective role of uremia from disease progression of the HCV infection. We suggest that the possible explanation is a suppressive effect of uremic milieu through a mediator (hepatocyte growth factor?) could slower the course of HCV infection in HD patients. Interestingly we found duration of HCV infection was shorter in patients with severe lobular necroinflammatory activity and correlated negatively with AST levels. The patients with longer HD duration were expected to have a longer HCV infection duration. This finding might be an indirect reflection of the link between HD and HCV duration.
CONCLUSION
Although there is a high degree of liver involvement, cirrhosis is a relatively less frequent finding in HD patients. Serum aminotransferases and ferritin levels but not the pattern of HCV viremia is predictors of necroinflammatory activity in liver biopsy specimens.
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