Noninvasive Tools to Assess Hepatic Fibrosis: Ready for Prime Time?

Often regarded as the gold standard for fibrosis assessment, liver biopsy does carry associated risks given its invasive nature. Moreover, liver biopsy is not a true gold standard owing to interobserver and intra-observer variability and the small amount of tissue that is typically obtained with this procedure. Advances in the development of serologic tests and conventional imaging techniques have been shown to reduce the need for liver biopsy for diagnosing hepatic fibrosis. More commonly, it is a tool that is now reserved for evaluating indeterminate noninvasive tests or excluding features of particular diseases (eg, autoimmune hepatitis, steatohepatitis).

The noninvasive assessment of hepatic fibrosis has been a popular topic of discussion over the past decade. The ideal properties of a noninvasive test include widespread availability, ease of use, cost-efficiency, reproducibility, and the ability to detect changes in fibrosis over time. Furthermore, the ability of noninvasive testing to identify intermediate to advanced histologic stages of fibrosis (stage F2 or higher) without liver biopsy is important as this is the usual threshold to start treatment in eligible subjects with chronic hepatitis C (HCV), for example. In addition, the identification of early stage cirrhosis by noninvasive testing allows for the timely implementation of disease management strategies (hepatocellular carcinoma and variceal screening) to reduce the likelihood of complications.

This article reviews the salient aspects of hepatic fibrogenesis as well as the diagnostic performance of serum markers and imaging techniques that are currently available for detecting hepatic fibrosis. Finally, will provide suggestions as to how these noninvasive methods can be incorporated into routine clinical practice.

Pathogenesis of Hepatic Fibrosis

The hepatic stellate cell is thought to play an integral role in hepatic fibrosis. When in a quiescent state, stellate cells serve as storage reservoirs for retinol (a precursor of vitamin A) and other lipid soluble substances. Moreover, they control extracellular matrix (ECM) turnover and regulate sinusoidal blood flow. Additional fibrogenic cells involved with hepatic fibrogenesis are derived from portal fibroblasts, circulating fibrocytes, bone marrow, and epithelial–mesenchymal cell transition. The proportion of fibrogenic cells from these various sources likely depends on the etiology of liver disease. For example, stellate cells are mainly involved when the damage is centered within the hepatic lobule. On the other hand, portal fibroblasts are observed to contribute more in cholestatic liver disease and ischemia.

A variety of mediators have been shown to promote ongoing stellate cell activation and fibrogenesis, with platelet-derived growth factor and transforming growth factor-β described as 2 of the major cytokines involved with this process. Stellate cell activation occurs through several additional pathways as well. Oxidative stress in the form of reactive oxygen species can activate stellate cells. This pathway may be of particular relevance in alcoholic liver injury, nonalcoholic fatty liver disease, and iron overload syndromes. Parenchymal cell apoptotic bodies can induce an inflammatory response that activates stellate cells as well. Bacterial lipopolysaccharide can elicit a fibrogenic response by binding to stellate cells via Toll-like receptor 4. Lastly, paracrine stimuli from adjacent cell types (macrophages, sinusoidal endothelium, and hepatocytes) can also aid in the transformation of stellate cells from a quiescent to an activated state.

Once activated, stellate cells and fibroblasts transform into myofibroblasts, which are cells that contain contractile filaments. Myofibroblasts have the capacity to alter the composition of the ECM. Progressive changes in the ECM include a change from type IV collagen, heparan sulfate proteoglycan, and laminin to types I and III collagen. Subsequently, ECM accumulates owing to its increased synthesis and decreased degradation. Fibrogenesis is further propagated by positive feedback mechanisms that arise from changes in ECM composition. Changes in membrane receptors (eg, integrins), activation of cellular matrix metalloproteases and increasing matrix stiffness serve as stimuli to perpetuate stellate cell activation. It is this dynamic production and turnover of matrix, as well as increases in matrix stiffness, that form the basis for clinical techniques to noninvasively assess the extent of hepatic fibrosis.

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