Steatosis is a frequent finding in HCV-infected liver transplant recipients, with about one–third demonstrating at least mild steatosis at approximately one year post-LT. Three factors were found to be associated with steatosis. HCV genotype 3 was an expected finding since this genotype is associated with “virologic” steatosis.18
The association between donor age and steatosis at one-year post-LT is new and may indicate that donor factors rather than host factors are important in determining the early presence of steatosis on post-LT liver biopsy. As expected, post-LT steatosis was associated with some comorbidities of the metabolic syndrome, since nonalcoholic fatty liver disease (NAFLD) is felt to be the hepatic manifestation of the metabolic syndrome.19
Pre-LT HTN as a predictor of steatosis at index liver biopsy may be an indicator of individuals who have the propensity to develop the metabolic syndrome, particularly since HTN is generally an infrequent finding in patients with ESLD due to high levels of circulating vasodilatory substances.20
The lack of association between DM and steatosis was somewhat surprising, although in the non-LT setting, not all studies have demonstrated an independent relationship between insulin resistance and steatosis.21
Because of a low frequency of hyperlipidemia both pre- and post-LT, we were unable to detect an association between this condition and other comorbidities of the metabolic syndrome or with steatosis.
Importantly, we found that post-transplant steatosis was a strong and independent predictor of significant fibrosis. Our ability to detect a “dose-response” with greater degrees of steatosis was limited by the small proportions of individuals with grades 2 and 3 steatosis. The association between steatosis and fibrosis was present, despite adjustment for metabolic factors such as pre-existing or new-onset DM and HTN. Previous studies evaluating the relationship between steatosis and fibrosis have been limited by small sample size and/or lack of adjustment for metabolic confounders such as DM.22, 23
As has been documented in multiple prior studies, DM (both pre-existing and new-onset) was associated with increased risk of fibrosis progression in individuals infected with HCV.3,24
Our findings contrast with those reported by Veldt et al6
, likely due to differences in study populations, analytic methods and endpoints between the two studies. Veldt et al reported a higher prevalence of mild to moderate steatosis (39%) than our study but they evaluated steatosis at any time from 4 months to years post-transplantation. Our evaluation of steatosis was at a single early time point post-LT to specifically determine the temporal relationship between steatosis and subsequent fibrosis. Additionally, the Veldt study examined diabetes and insulin resistance at 4 months post-LT whereas our study focused on pre-LT DM as a predictor of outcomes.
HTN alone has not previously been associated with fibrosis progression in HCV-infected individuals, and the pathophysiologic basis for promotion of fibrosis development is unclear. While antihypertensive medications such as angiotensin receptor blockers have been shown to improve inflammation and fibrosis in individuals with NASH, it is unclear if this phenomenon would apply to HCV-infected LT recipients.25
Comorbidities of the metabolic syndrome, such as hypertension, may correlate with a more severe systemic inflammatory state.26
Altered levels of several different adipocytokines (e.g., adiponectin, TNF-α, plasminogen activator inhibitor type 1) have been observed in individuals with the metabolic syndrome, as well as in those with NAFLD, and may mediate hepatocellular damage in the setting of steatosis.27–29
Our finding of an association between sirolimus use and risk of significant fibrosis among patients with steatosis was unexpected. Animal studies indicate that sirolimus has antifibrotic properties, and suggest this drug may have potential benefit in recurrent fibrotic diseases such as HCV.29–31
However, hypertriglyceridemia is a known adverse effect of sirolimus,32
which may contribute to the risk of hepatic steatosis, though a direct association between sirolimus and hepatic steatosis has not been reported. Finally, because individuals who were treated with sirolimus had more episodes of treated rejection, sirolimus treatment may be a surrogate marker for treated acute rejection that involved more use of corticosteroids, although our sample size limited such subgroup analyses. It is possible that rejection severe enough to warrant the addition of sirolimus to the immunosuppressant regimen is a factor that is strong enough may drive fibrosis progression, overriding any potential antifibrotic effects of sirolimus, particularly if steatosis is present. Alternatively, individuals who are treated with sirolimus may possess unmeasured factors that make them more susceptible to both the development of steatosis and advanced fibrosis.
A potential limitation in our study is the lack of a donor liver biopsy for all subjects. However, donor age may be used as a surrogate for hepatic steatosis, since increasing age is associated with higher prevalence of hepatic steatosis.11
Importantly, the prevalence of donor DM and median donor BMI were similar between steatosis groups, suggesting no obvious differences in potential risks of steatosis between donor groups. Finally, the existing data regarding donor steatosis and HCV recurrence and fibrosis progression is mixed, possibly related to differences in categorization of steatosis33–34
Our use of single center data may limit the generalizability of the results, particularly in centers with different immunosuppression strategies. Because we excluded individuals with greater than fibrosis stage 2 on the index biopsy and those without biopsies during the first 6–18 months post-LT, we may have excluded those with both the most severe disease, as well as those with mild disease. Also, because our classification of DM, HTN, and HL were based on the use of medications to treat these conditions, it is likely that the true prevalence of these conditions is higher than we observed. However, because we would expect this misclassification to be random and evenly distributed between the steatosis and no steatosis groups, the relationship between steatosis and fibrosis progression should not be affected. Finally, given the challenges in distinguishing 5% steatosis from that slightly more or less than 5% by microscopy, other methods of assessment such as digital quantification may be more useful, at least in the research setting35
. However, the relevance of such methods in clinical practice has not been established.
In conclusion, we have shown that steatosis is a frequent finding in HCV-infected transplant recipients and its presence early post-LT predicts a greater risk of subsequent fibrosis progression. Moreover, we found that the association between steatosis and risk of significant fibrosis remained even after adjusting for other components of the metabolic syndrome. Thus, a finding of steatosis early post-LT should serve as a marker of the need for closer histological follow-up and possible consideration of early antiviral intervention. An important future area of research is to determine if modification of the metabolic syndrome and/or steatosis can reduce the HCV transplant recipients’ risk of fibrosis progression.