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Discussion
Patients with chronic HCV infection and ESRD had significantly lower serum aminotransferase and less hepatic necrosis, inflammation and fibrosis than control patients with HCV and no renal disease. There were no racial differences in serum liver tests and liver histology among HCV patients with ESRD. AA race, age <50 years, ESRD and a serum alkaline phosphatase level <120 IU/L were independently associated with lower odds of advanced liver fibrosis and cirrhosis (HAI-IV score >3) in multivariable regression analysis.
Prior studies have found significantly lower serum ALT and AST and less severe hepatic inflammation and fibrosis in patients with HCV and ESRD. However, most of these studies were limited by small sample sizes and lack of control for other risk factors for liver fibrosis. We studied the association between ESRD and liver necro-inflammation, fibrosis and overall histological activity in a large, racially diverse cohort. Thus, the study provided a unique opportunity to examine the potential confounding effects of race and ESRD on HCV-related liver disease expression.
In keeping with previous studies, we observed lower serum AST, ALT, albumin, total bilirubin and less necro-inflammation and fibrosis in ESRD patients with HCV compared to control patients with HCV and no renal disease. In addition, both severe portal inflammation (HIA-III > 3) and liver fibrosis (HIA-IV > 3) were less prevalent among patients with ESRD. Among patients with ESRD, HAI scores did not differ between AAs and CAs. In contrast, among patients without ESRD, AA race was independently associated with less liver fibrosis.
Variables associated with more advanced liver fibrosis in HCV patients without renal disease have been extensively characterized in previous studies and include Caucasian race, older age at the time of infection, longer duration of HCV infection, obesity, hepatic steatosis and alcohol abuse. However, the variables associated with advanced liver fibrosis in patients with HCV and ESRD are not well understood. Any degree of hepatic steatosis and a platelet count <130 × 10/L were associated with advanced liver fibrosis (HAI-IV > 3) in a study by Hu et al. In the present study, AA race, ESRD, age <50 years and lower serum alkaline phosphatase level were independently associated with lower odds for moderate to severe liver fibrosis (bridging fibrosis or cirrhosis).
It is well established that AAs with chronic HCV infection and no renal disease have milder liver necro-inflammation and fibrosis than CA patients with similar durations of HCV infection. These racial differences in liver histology are not explained by a variance in hepatic iron content. It has been postulated that a less vigorous HCV-specific CD4 T-cell response in AAs and racial differences in HLA haplotypes may explain the lower degree of liver injury and disease severity in AA patients. AA race was also associated with lower odds for advanced fibrosis in patients without renal disease, but not in patients with ESRD. These observations indicate that lower liver fibrosis level in patients with ESRD was not explained by the higher proportion of AAs in this subgroup. However, it is possible that an association between race and liver fibrosis could be obscured by the smaller number of CA patients with ESRD.
A serum alkaline phosphatase <120 IU/L was associated with lower odds for advanced liver fibrosis in patients with and without ESRD in the current study. A lower serum alkaline phosphatase was one of the several variables associated with less advanced (Ishak stage 0–2) liver fibrosis in a report by Fontana et al., although the biological basis has not been defined. Several prior studies have found an association between alcohol abuse and more advanced liver fibrosis and higher mortality rates in patients with chronic HCV. In contrast, alcohol abuse, defined as greater than two alcoholic beverages per day, was not an independent predictor of more advanced liver fibrosis in the current study. These results should be interpreted with caution, as they are based on patient recall, and we were not able to quantify alcohol intake and exposure above the two beverage threshold.
The pathophysiologic basis for differential expression of liver necro-inflammation and fibrosis in HCV patients with and without ESRD is poorly understood. One study suggested that the increase in hepatocyte growth factor levels in HCV-infected patients with ESRD protects liver cells against HCV-induced apoptosis and stimulates hepatocyte proliferation. HCV infection among haemodialysis patients was proposed to be associated with decreased plasma oxidative load. Another study assessed the histopathological features of hepatitis C in renal transplant candidates, comparing changes among haemodialysis patients compared to those with predialysis chronic renal disease. Patients on haemodialysis exhibited less necro-inflammation and fibrosis. This finding may suggest a role for haemodialysis in delaying liver fibrosis associated with HCV infection in patients undergoing haemodialysis.
This study has several limitations. Because of the retrospective design, data on duration of HCV infection, chronic renal disease and ESRD, duration of dialysis, aetiology of renal disease, HCV genotype and viral load, and prior HCV treatment were not collected. Age has been viewed as a surrogate marker for the duration of HCV infection in patients without ESRD, but is not a reliable indicator of length of infection in ESRD patients who often have nosocomial transmission during haemodialysis. ESRD patients in this study represent those were referred to examine their eligibility for renal transplantation, but not renal and liver transplantation. This excludes ESRD patients with more advanced fibrosis or cirrhosis. On the other hand, patients on the liver transplantation waiting list were also excluded from the control group to avoid referral bias.
In conclusion, our study demonstrated that HCV patients with ESRD exhibit less hepatic necro-inflammation and fibrosis than those without renal disease. Milder hepatic necro-inflammation and fibrosis in patients with ESRD is not explained by the higher prevalence of renal disease in AAs
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