How accurately and how early can we predict rapid fibrosis progression in hepatitis C virus–infected patients after liver transplantation?^†

Liver fibrosis is the most relevant variable for assessing the degree of liver damage in chronic liver diseases. Collagen deposition is the result of different inflammatory processes occurring within the liver, and its progression determines the appearance of portal hypertension and clinical decompensation. Although liver biopsy is essential for establishing a diagnosis, its value in quantifying the degree of liver damage (particularly of liver fibrosis) is controversial. Sampling errors, intraobserver and interobserver variability, and associated morbidity are some of the limitations of liver biopsy.1, 2 This is even more important in liver transplant recipients, for whom repeated liver biopsies are relevant during follow-up.

Abbreviations

HA, hyaluronic acid; HCV, hepatitis C virus; LT, liver transplantation.

For the aforementioned reasons, the assessment of liver fibrosis by noninvasive markers is an ongoing topic of research in hepatology. Noninvasive diagnosis of liver fibrosis should rely on markers that are easy to obtain, reproducible, and accurate for predicting different fibrosis stages. Significant progress has been made in the field of viral hepatitis, in which the noninvasive evaluation of liver fibrosis is common in clinical practice. Moreover, recent studies have evaluated the impact of antiviral therapy on liver fibrosis in patients with chronic hepatitis C and support the idea that fibrosis, even in advanced stages, may be reversible.3, 4 Evaluation of liver damage (fibrosis changes) after antiviral therapy should ideally be performed by noninvasive methods.

Assessing the value of noninvasive markers in the setting of hepatitis C virus (HCV) infection after liver transplantation (LT) is scientifically attractive but difficult. It is attractive because LT is a unique model of accelerated fibrosis progression: the time to develop advanced fibrosis (cirrhosis) can occur even before 1 year following graft transplantation.5-7 It is difficult because of the high number of variables that may influence fibrosis progression in these patients: ischemic problems, rejection, coinfections, and different doses and types of immunosuppressive agents. In most studies analyzing the impact of these variables on fibrosis progression, they are not recorded prospectively, and this poses complexity in the interpretation of data.

The study by Pungpapon et al.8 suggests that serum hyaluronic acid (HA) and YKL-40, measured at 3-8 months after LT, can accurately identify HCV-infected liver transplant recipients with rapid fibrosis progression. As stated previously, this is a relevant topic in the field of transplantation, and the study adds important information to the field. Let us analyze in detail some methodological points of the study. First, at this early stage of transplantation (3-8 months), the potential insults to the liver are multiple and may be related not only to HCV graft infection but also to graft perfusion (arterial complications), biliary function (strictures and leaks), other viral infections, and immune response (rejection). The authors did not find any significant differences between rapid and slow “fibrosers” with respect to ischemia times, donor/recipient cytomegalovirus mismatch, immunosuppressive agents, and incidence of allograft rejection. Nevertheless, it would have been extremely relevant to include a control group in order to see if these variables influence serum HA and YKL-40 levels in non–HCV-transplanted patients. A second point that requires further analysis is the time at which fibrosis progression was evaluated: rapid fibrosis progression was defined as an increase in the fibrosis score (Ishak) ≥ 2 points observed 2 to 4 years after the first liver biopsy. Does this definition really identify rapid fibrosers? Are patients who progress from a fibrosis score of 0 to 2 comparable to those in whom fibrosis increases from a score of 3 to 6? Is it adequate to identify rapid fibrosis progression 4 years after transplantation? Finally, the small sample size of the cohort magnifies the limitations of liver biopsy for assessing liver fibrosis: sampling errors and intraobserver/interobserver variability. The inclusion of other markers of disease progression (such as the hepatic venous pressure gradient or the development of clinical decompensation) might have circumvented some of these problems.9

Despite the aforementioned limitations, the accuracy of these 2 markers in predicting rapid fibrosis progression was very high, and their determination is technically neither difficult nor expensive. HA, a component of extracellular matrix, is a glucosaminoglycan synthesized by the mesenchymal cells and degraded by hepatic sinusoidal cells by a specific receptor-mediated process. In liver diseases, HA is synthesized by the hepatic stellate cells and is an indicator of the fibrogenic process. Because severe liver fibrosis causes sinusoidal capillarization, clearance of HA is diminished, and thus HA levels increase because of enhanced production and reduced clearance. Accordingly, HA is expected to increase in patients with hepatitis C recurrence and advanced fibrosis stages. Different studies have shown that HA has the best discriminative value for identifying patients with already established cirrhosis or advanced hepatic fibrosis.10, 11 A question that arises is why HA increases at early stages of liver fibrosis in these patients. A possible explanation is the high speed of the fibrogenic process in HCV-infected liver transplant recipients. In addition, the important inflammatory reaction that takes place during acute hepatitis C shortly after LT (which is associated with rapid fibrosis progression6) may also increase HA serum levels. Nevertheless, increases in HA not related to fibrogenesis should also be considered in this setting. It is well documented that HA may increase with rheumatoid arthritis, scleroderma, psoriasis, sepsis, and impaired renal function.12 The latter are relatively common complications in liver transplant patients and should be taken into account when HA levels are measured. In addition, there is no information on the effects of the inflammatory response to non–HCV-related insults (rejection and viral infections) on HA levels. Finally, there are few data on the effects of steroids on HA serum levels: it could be speculated that high prednisone doses shortly after LT may lower HA levels if there is a reduction in the inflammatory response to HCV infection. Actually, it has been shown that methylprednisolone attenuates the inflammatory response and decreases HA levels after ischemic reperfusion injury and rejection.13

YKL-40 is a human cartilage glycoprotein produced in a wide variety of cells, including chondrocytes, synovial cells, macrophages, and neutrophils. Immunohistochemical studies of liver biopsies have shown positive staining for YKL-40 in areas with fibrosis (particularly in those with ongoing fibrogenesis).14 YKL-40 can also be considered an inflammation marker, and this explains its high serum levels in diseases with inflammation, tissue remodeling, fibrosis, and cancer.15, 16 Although the biology of YKL-40 is not well understood, in patients with chronic hepatitis C, serum YKL-40 levels correlate with the severity of fibrosis and with its progression over time, reflecting the tissue remodeling process.10, 16, 17 As mentioned for HA, it is very difficult to anticipate how all the inflammatory reactions occurring early after LT and the different treatments may influence the serum levels of these proteins.

All the aforementioned points emphasize the difficulties associated with the use of serum fibrogenesis markers in the setting of LT. However, hepatitis C recurrence after LT is currently the most important problem of LT programs, and any progress in this field is of particular relevance. It is imperative to notice that the efficacy and tolerance of the current antiviral treatment are far from optimal in HCV-infected LT recipients.18 Thus, the utilization of serum fibrosis markers to discriminate between patients with slow and rapid fibrosis progression after hepatitis C recurrence could be crucial for (1) avoiding unnecessary therapy in individuals with a good long-term outcome and (2) initiating early treatment in patients with a high probability of developing cirrhosis (and, more importantly, before the disease is too advanced to initiate interferon-based therapy). Despite the excellent predictive value of the markers used by Pungpapon et al.,8 a single determination of any serum fibrosis marker is probably not sufficient, and serial determinations would be advisable to disclose temporary variations or confirm fibrosis progression. Moreover, the combination of HA and YKL-40 with other noninvasive fibrosis markers (such as transient elastography) could increase their diagnostic accuracy in HCV-infected liver transplant recipients.19, 20 Once rapid fibrosers are identified, a liver biopsy is still necessary before antiviral treatment is started to exclude other potential causes of graft injury.